Compound, pharmaceutically acceptable salt or optical isomer thereof, method for preparing the same, and pharmaceutical composition for prevention or treatment of viral diseases containing same as active ingredient

ABSTRACT

The present invention relates to a novel compound, to a pharmaceutically acceptable salt or optical isomer thereof, to a method for preparing same, and to a pharmaceutical composition for the prevention or treatment of viral diseases containing same as an active ingredient. The novel compound according to the present invention not only has low cytotoxicity but also has excellent antiviral activity against picornavirus such as coxsackievirus, enterovirus, echovirus, poliovirus and rhinovirus, and thus can be effectively used as a pharmaceutical composition for the prevention or treatment of viral diseases such as infantile paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myitis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinus infection, or otitis media.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/651,656, now allowed, filed on Jun. 11, 2015, whichapplication is a national stage filing under 35 U.S.C. 371 ofInternational Patent Application No. PCT/KR2013/011668, filed on Dec.16, 2013, which application claims the benefit of priority of KoreanPatent Application No. 10-2013-0156409, filed Dec. 16, 2013, and ofKorean Patent Application No. 10-2012-0146081, filed Dec. 14, 2012, allof which are incorporated by reference in their entirety.

BACKGROUND

1. Technical Field Text

The present invention relates to novel compounds, pharmaceuticallyacceptable salts or optical isomers thereof, methods for preparing thesame, and pharmaceutical compositions for prevention or treatment ofviral diseases containing the same as active ingredients.

2. Background Information

Picornaviruses are non-enveloped, positive single-stranded RNA viruseswith an RNA genome 7.2-8.5 Kb long. These viruses are very small andglobular in shape with a size of about 22-30 nm, and were firstidentified a long time ago. Among the viruses belonging to the familyPicornaviridae are enteroviruses including rhinovirus, poliovirus,coxsackie virus A, coxsackie virus B, and echovirus, and hepatitis Avirus.

The diseases that picornaviruses, RNA viruses, cause are varied, rangingfrom respiratory diseases to digestive diseases, to circulatory diseasesand to dermal diseases, examples of which include poliomyelitis, acutehemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouthdisease, vesicular disease, hepatitis A, myositis, myocarditis,pancreatitis, diabetes, epidemic myalgia, encephalitis, flu, herpangina,and foot-and-mouth disease. However, there are no therapeutic agents forcuring these diseases. Most of the drugs under development are uncoatinginhibitors. Viruses belonging to the family Picornaviridae cause variousdiseases including the aforementioned respiratory diseases, which evokehygienic, social and economic issues. Picornaviruses are the maincausative agents of waterborne diseases. Being very stable and difficultto disinfect, they incessantly cause related viral diseases.

Human rhinoviruses (hRV) have been recently associated with the majorityof asthma exacerbations, and are known to exist even in bronchialtissues of many stable asthma patients. Comparison of respectivebronchial mucosa biopsy specimens taken from asthma and non-asthmapatients showed significantly higher frequencies of detection of humanrhinoviruses in the lower respiratory tract of asthma patients, comparedto non-asthma patients. It has also been reported that there iscorrelation between the presence of rhinovirus and the clinical severityof asthma. In addition, human rhinoviruses cause chronic obstructivepulmonary disease, pneumonia, sinusitis, and otitis media as well asasthma

Rhinoviruses are the main causative of the common cold whileenterovirus-induced diseases include meningitis, respiratory tractinfection, etc. Extensive effort to provide vaccination againstpoliovirus has significantly reduced the onset of poliomyelitisworldwide, but there are still reports of cases of the disease in Niger,Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A is nowpossible to control to some degree thanks to vaccines for hepatitis Aviruses. However, no vaccines for coxsackieviruses, echoviruses, orrhinoviruses have been developed, thus far.

Particularly, coxsackievirus B is a main cause of myocarditis, which maydevelop, in serious cases, into idiopathic dilated cardiomyopathy, whichrequires heart transplantation.

Enviroxime derivatives are considered the most promising candidate witha broad anti-enterovirus- and anti-rhinovirus activity. Enviroximeinterferes with the synthesis of plus-strand RNA by binding to the virusprotein 3A that is required for the formation of RNA intermediates inthe virus reproduction (Heinz B A and Vance L M: J Virol, 1995, 69(7),4189-97). In clinical studies, however, the compound was observed tohave few or no therapeutic effects, with detection of insufficientpharmacokinetics and unwanted side effects (Miller F D et al.:Antimicrob Agents Chemother, 1985, 27(1), 102-6).

The protease inhibitor AG 7088 has been developed on the basis of theknowledge about the sophisticated structure and function of the viralprotease 2C. In the cell culture in the nanomolar concentration range,AG 7088 has shown an effect against 48 rhinovirus types andcoxsackievirus A21, B3, enterovirus 70 and echovirus 11 (Pattick A K etal.: Antimicrobila Agents Chemother, 1999, 43(10), 2444-50).

Thanks to the clarification of the molecular structure of the viralcapsids, the preconditions for a purposeful design of capsid blockers,the “WIN substances”, have been obtained (Diana G D: Curr Med Chem 2003,2, 1-12). They inhibit the adsorption and/or the uncoating ofrhinoviruses and enteroviruses. Some of the WIN substances have a highlyspecific effect only against individual genera or virus types of thepicornaviruses. Other derivatives inhibit the replication both ofrhinoviruses and enteroviruses. Arildone, disoxaril and pirodavirbelong, for example, to the WIN substances. These compounds showed verygood antiviral effects in the cell culture. However, a poor solubility(arildone), low bioavailability (arildone and disoxaril), a rapidmetabolization and excretion (disoxaril and WIN 54954) as well as sideeffects, such as skin rash (WIN 54954), made a clinical applicationimpossible.

Pleconaril, another kind of WIN substance, has a very good oralbioavailability and after its binding to the hydrophobe pocket in theviruscapsid, it inhibits the penetration of rhino-, echo- andcoxsackieviruses (Pevear D C et al.: Antimicrob Agents Chemother 1999,43(9), 2109-15; McKinlay M A et al.: Annu Rev Microbiol 1992, 46,635-54). Therefore, pleconaril is potentially effective against a broadspectrum of virus diseases, ranging from the common cold to the viralmeningitis or myocarditis. Resistances were observed for rhinoviruses,enterovirus 71 and coxsackievirus B3 (Ledford R M et al.: J Virol 2004,78(7), 3663-74; Groarke J M et al.: J Infect Dis 1999, 179(6), 1538-41).However, the proven therapeutic effect was not sufficient for theregistration of pleconaril (Picovir, Viropharma, USA) as an agent forthe treatment of rhinovirus infections in the USA. In March 2002, acorresponding application was refused by the Food and DrugAdministration (FDA) because therapy success was too low and sideeffects were observed.

BTA-798 was found to have higher antiviral activity than pleconaril, asevaluated in vitro and in vivo efficacy with rhinoviruses, and is nowunder clinical study (Ryan, J. et al. Antiviral Res [18th Intl ConfAntiviral Res (Apr. 11-14, Barcelona) 2005] 2005, 65(3): Abst LB-11).

However, no antiviral drugs for use in the treatment of entero- orrhinoviruses have been developed that have gained approval yet.

Thus, while the present inventors were researching antiviral compoundsagainst picornaviruses including coxsackcevirus, enterovirus, echovirus, polio virus and rhino virus, they synthesized the novel compoundsexpressed by Formula 1 of the present specification and verified thatsaid compounds had excellent antiviral activities against picornavirusesincluding coxsackievirus, enterovirus, echo virus polio virus and rhinovirus to complete the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS AND THE PRESENTLY PREFERREDEMBODIMENTS

The objective of the present invention is to provide the compoundexpressed in Formula 1 or Formula 2 of the present specification, aspharmaceutically acceptable salt thereof or an optical isomer thereof.

Another objective of the present invention is to provide a method forpreparing the compound expressed in Formula 1 or Formula 2 above.

Still another objective of the present invention is to provide apharmaceutical composition for prevention or treatment of a viraldisease comprised of the compound, the pharmaceutically acceptable saltthereof or the optical isomer thereof as an active ingredient.

To achieve the above objectives, the present invention provides thecompound expressed in Formula 1 or Formula 2 below, a pharmaceuticallyacceptable salt thereof or an optical isomer thereof.

In Formulae 1 and 2 above,

R¹, R², R³, R^(4a), R^(4b), R^(4c) and R⁵ are respectively as defined inthe present specification, and the compounds expressed in Formula 1 andFormula 2 above exist in an equilibrium state with each other.

In addition, the present invention provides, as shown in ReactionEquation 1 below, a method for preparing the compound expressed inFormula 1 or Formula 2 above, comprising a step (step 1) in which thecompound expressed in Formula 3 or Formula 4 and the compound expressedin Formula 5 are placed in a solvent with a reaction catalyst and thenstirred.

In Reaction Equation 1 above,

X^(a) is —OH or —NH₂, and

R¹, R², R³, R^(4a), R^(4b), R^(4c) and R^(4d), R⁵, X and L arerespectively as defined in Formulae 1 and 2 above.

Furthermore, the present invention provides a pharmaceutical compositionfor prevention or treatment of a viral disease containing the compoundexpressed in Formula 1 or Formula 2 above, the pharmaceuticallyacceptable salt thereof or the optical isomer thereof as an activeingredient.

Advantageous Effects

The compound expressed in Formula 1 or Formula 2 according to thepresent invention which is in an equilibrium state with each other hasnot only low cytotoxicity but also very excellent antiviral activitiesagainst picornaviruses including coxsackieviruses, enteroviruses,echoviruses, polioviruses, and rhinoviruses so may be usefully used asthe pharmaceutical composition for prevention or treatment of viraldiseases including poliomyelitis, acute hemorrhagic conjunctivitis,viral meningitis, hand-foot-and-mouth disease, vesicular disease,hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemicmyalgia, encephalitis, flu, herpangina, foot-and-mouth disease, asthma,chronic obstructive pulmonary disease, pneumonia, sinusitis or otitismedia.

Best Mode for Implementing the Invention

In the following is described the present invention in detail.

The present invention provides the compound expressed in Formula 1 orFormula 2 below, the pharmaceutically acceptable salt thereof or theoptical isomer thereof.

In Formulae 1 and 2 above,

R¹ is —H, linear or branched C₁₋₆ alkyl or —NO₂;

R² is —H, linear or branched C₁₋₆ alkyl or —NH₂;

R³ is —H, or linear or branched C₁₋₆ alkyl;

R^(4a), R^(4b), R^(4c) and R^(4d) are independently —H or linear orbranched C₁₋₆ alkyl;

X is —O—, —NH— or —NR⁶—, wherein the R⁶ is linear or branched C₁₋₆alkyl;

L is a single bond,

wherein R¹¹ is ═O, ═NH or ═S, and a, b, c, d and e are independentlyintegers of 0-5;

R⁵ is —CN; linear or branched C₁₋₁₀ alkyl; linear or branched C₁₋₁₀haloalkyl; phenyl; phenyl linear or branched C₁₋₆ alkyl; phenyl linearor branched C₁₋₆ alkenyl; 5-6 atom heteroaryl including one or moreheteroatoms of one or more species selected from a group consisting ofN, O and S; 5-8 atom hetero cycloalkyl including one or more heteroatomsof one or more species selected from a group consisting of N, O and S;5-8 atom heterocycloalkenyl including one or more heteroatoms of one ormore species selected from a group consisting of N, O and S;

wherein the phenyl group in the phenyl, phenyl linear or branched C₁₋₆alkyl, and phenyl linear or branched C₁₋₆ alkenyl, may be substitutedwith one or more substituents of one or more species selected from agroup consisting of —OH, halogen, linear or branched C₁₋₆ alkyl, linearor branched C₁₋₆ alkoxy, and —NO₂,

wherein the heteroaryl, heterocycloalkyl, and heterocycloalkenyl, may besubstituted with one or more substituents of one or more speciesselected from a group consisting of —OH, halogen and linear or branchedC₁₋₆ alkyl,

R⁷ and R⁸ are independently —H, linear or branched C₁₋₆ alkyl,non-substituted phenyl, phenyl substituted with one or more linear orbranched C₁₋₆ alkyl,

R⁹, R¹⁰ and R¹¹ are independently —H or linear or branched C₁₋₁₀ alkyl,

Z is —O— or —S—,

f, g, h and i are independently integers of 0-5; and

the compound expressed in Formula 1 and the compound expressed inFormula 2 above exist in a state of equilibrium to each other.

Preferably,

the R¹ is —H, linear or branched C₁₋₃ alkyl or —NO₂;

R² is —H, linear or branched C₁₋₃ alkyl or —NH₂;

R³ is —H, or linear or branched C₁₋₃ alkyl;

R^(4a), R^(4b), R^(4c) and R^(4d) are independently —H or a linear orbranched C₁₋₄ alkyl;

X is —O—, —NH— or —NR⁶—, wherein the R⁶ is a linear or branched C₁₋₃alkyl;

L is a single bond,

wherein R¹¹ is ═O, ═NH or ═S, and wherein a, b, c, d and e areindependently integers of 0-3;

R⁵ is —CN; linear or branched C₁₋₈ alkyl; linear or branched C₁₋₈haloalkyl; phenyl; phenyl linear or branched C₁₋₃ alkyl; phenyl linearor branched C₁₋₃ alkenyl; 5-6 atom heteroaryl including one or morehetero atoms of one or more species selected from a group consisting ofN, O and S; 5-6 atom heterocycloalkyl including one or more heteroatomsof one or more species selected from a group consisting of N, O and S;5-6 atom heterocycloalkenyl including one or more heteroatoms selectedfrom a group consisting of N, O and S;

wherein the phenyl group in the phenyl, phenyl linear or branched C₁₋₃alkyl, and phenyl linear or branched C₁₋₃ alkenyl, may be substitutedwith one or more substituents of one or more species selected from agroup consisting of —OH, halogen, linear or branched C₁₋₃ alkyl, linearor branched C₁₋₃ alkoxy, and —NO₂,

wherein the heteroaryl, heterocycloalkyl, and heterocycloalkenyl may besubstituted with one or more substituents selected from a groupconsisting of —OH, halogen and linear or branched C₁₋₃ alkyl,

the R⁷ and R⁸ are independently —H, linear or branched C₁₋₄ alkyl,phenyl that is non-substituted phenyl, phenyl substituted with one ormore linear or branched C₁₋₃ alkyl,

R⁹, R¹⁰ and R¹¹ are independently —H or linear or branched C₁₋₆ alkyl,

Z is —O— or —S—, and

f, g, h and i are independently integers of 0-3.

More preferably,

R¹ is —H or —NO₂;

R² is —H or —NH₂;

R³ is —H or methyl;

R^(4a), R^(4b), R^(4c) and R^(4d) are independently —H, methyl orisopropyl;

X is —O—, —NH—, or —N(CH₃)—;

L is a single bond,

R⁵ is —CN, linear or branched C₁₋₆ alkyl, linear halogen C₁₋₂ alkyl,phenyl, phenyl linear C₁₋₂ alkyl, phenyl linear C₂ alkenyl, 5-6 atomhetero aryl including one or more heteroatoms of one or more speciesselected from a group consisting of N, O and S, 6 atom heterocycloalkylincluding one or more heteroatoms of one or more species selected from agroup consisting of N, O and S, 5 atom hetero cycloalkenyl including oneor more heteroatoms of one or more species selected from a groupconsisting of N, O and S

wherein the phenyl group in the phenyl, phenyl linear C₁₋₂ alkyl, andphenyl linear C₂ alkenyl, may be substituted with one or moresubstituents of one or more species selected from a group consisting of—OH, methyl, methoxy and —NO₂,

wherein the heterocycloalkyl may be substituted with methyl,

R⁷ and R⁸ are independently —H, methyl, ethyl, propyl, isopropyl,dimethyl phenyl,

R⁹, R¹⁰, and R¹¹ are independently —H, methyl, ethyl or t-butyl,

Z is —O— or —S—, and

f, g, h and i are independently integers of 0-2.

Examples of the compound expressed in Formula 1 above may include thefollowing compounds:

-   1)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)-2-(1H-indol-3-yl)-2-oxo    acetamide;-   2)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-(thiopen-2-yl)acetamide;-   3)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-3-(2-nitrophenyl)-2-oxo    propanamide;-   4)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    propanamide;-   5)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    pentanamide;-   6)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    octanamide-   7)    2-(furan-2-yl)-6)N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    acetamide;-   8)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indol-3-yl)-2-oxo    acetamide;-   9)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-3-(4-hydroxyphenyl)-2-oxo    propanamide;-   10)    N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indol-3-yl)-2-oxo    acetamide;-   11)    N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl    acetamide;-   12)    N-(4b-hydroxy-7,8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl    acetamide;-   13)    N-(4b-hydroxy-7,8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-(1H-indol-3-yl)-2-oxo    acetamide;-   14)    N-(4b-hydroxy-7,8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indol-3-yl)-2-oxo    propanamide;-   15)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl    acetamide;-   16)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl    acetamide;-   17)    N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-4-(methylthio)-2-oxo    butanamide;-   18)    4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl    propyl carbamate;-   19)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    propanamide;-   20)    N1-(2,6-dimethylphenyl)-N2-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)oxal    amide;-   21)    N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2,N2-dimethyl    oxal amide;-   22)    N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    propanamide;-   23)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-(3,4,5-trimethoxyphenyl)acetamide;-   24)    (E)-4-(3,4-dimethoxyphenyl)-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxobut-3-enamide;-   25)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-(2-nitrophenyl)-2-oxo    propanamide;-   26)    N1-(2,6-dimethylphenyl)-N2-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)oxal    amide;-   27)    N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-methyl    oxal amide;-   28)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3    methyl-2-oxo pentanamide;-   29)    N-(4b-hydroxy-7-isopryl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-2-oxo    pentanamide;-   30)    N1-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-N2-dimethyl    oxal amide;-   31)    N1-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2,    N2-dimethyl oxal amide;-   32) Ethyl    2-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxo    acetate;-   33) Ethyl    2-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxo    acetate;-   34)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    pentanamide;-   35)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    octanamide;-   36) Ethyl    2-((1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxo    acetate;-   37)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,3-dimethyl-2-oxo    butanamide;-   38) N-(4b    hydroxyl-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-4-methyl-2-oxo    pentanamide;-   39)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenyl    butanamide;-   40)    N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-2-oxo    pentanamide;-   41)    3-bromo-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    propanamide;-   42)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2,4-dioxo-4-(pyridyn-4-yl)butanamide;-   43)    4-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-4-oxo    butanoic acid;-   44)    N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N4,    N4-dimethyl succinamide;-   45)    N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N4-isopropyl    succinamide;-   46)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)cyanamide;-   47)    N1-(4-amino-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-(2,6-dimethylphenyl)oxal    amide;-   48)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(4-methylpiperazin-1-yl)-2-oxo    acetamide;-   49)    N-(1-amino-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-4-methyl-2-oxo    pentanamide;-   50)    N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    hexanamide;-   51)    N-(4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2    mesityl-2-oxo acetamide;-   52)    N-(1-amino-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo    pentanamide;-   53)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenyl    butanamide;-   54)    N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-mesityl-2-oxo    acetamide;-   55) N,N′-di-tert-butoxycarbonyl    [1]-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]guanidine;-   56)    Tert-butyl(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)ethan-1,2-diyl    dicarbamate;-   57)    4-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-4-oxo    butanoic acid;-   58)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)2-oxo-2-(3,4,5-trimethoxyphenyl)acetamide;-   59)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenyl    butanamide;-   60)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetimide    amide;-   61)    1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)thiourea;-   62)    7-isopropyl-4b-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl    ethyl carbamate;-   63)    tert-butyl(2-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxoethyl)carbamate;-   64)    2-amino-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide;-   65)    4b-hydroxy-7,8-dimethyl-9b-(methylamino)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one;-   66) N-tert    butoxycarbonyl[N3-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]guanidine;-   67)    N,N′-di-tertbutoxycarbonyl[1-(4b-hydroxy-7,8-dimethyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]-1-methyl    guanidine;-   68)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)thiopene-2-sulfonamide;-   69)    N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)benzene    sulfonamide;-   70)    4b-hydroxy-7,8-dimethyl-9b-(pyridin-2-ylamino)-4b,9b)dihydro-10H-indeno[1,2-b]benzofuran-10-one;-   71)    N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)propane-1-sulfonamide;-   72)    1-chloro-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)methane    sulfonamide;-   73)    9b-((4,5-dihydrothiazol-2-yl)amino)-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno-[1,2-b]benzofuran-10-one;-   74)    4b-hydroxy-7-isopropyl-9b-(oxazol-2-ylamino)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one;    and-   75)    4b-hydroxy-7-isopropyl-9b-(pyridin-2-ylamino)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one.

The compounds expressed in Formula 1 or Formula 2 above of the presentinvention may be used in the form of pharmaceutically acceptable salts;acid addition salts formed by pharmaceutically acceptable free acids areuseful. The expression “pharmaceutically acceptable salt” means anyorganic or inorganic salt of the basic compounds of Formula 1 or Formula2 if the side effects caused by the salt at an efficacious concentrationthat is relatively non-toxic and non-harmful to the patient do notdegrade the beneficial efficacy of the basic compounds of Formula 1 orFormula 2.

For the salts in organic acid and organic acids may be used as freeacids, and the inorganic acids used may include hydrochloric acid,bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoricacid and the organic acids used may include citric acid, acetic acid,lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonicacid, gluconic acid, succinic acid, tartaric acid, galacturonic acid,embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L)malic acid, maleic acid, methane sulfonic acid, ethane sulfonic acid,4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, ormalonic acid.

In addition, such salts include alkali metal salts (sodium salt,potassium salt, etc.) and alkaline earth metal salts (calcium salts,magnesium salt, etc.). For example, acid addition salts may includeacetate, aspartate, benzoate, besylate, bicarbonate/carbonate,bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate,formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate,mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate,orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogen phosphate, saccharate, stearate, succinate,tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine,calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium,meglumine, alamine, potassium, sodium, tromethamine, and zinc salt, andhydrochloride and trifluoro acetate among them are preferred.

The acid addition salts according to the present invention may beprepared by typical methods. For example, they may be prepared bydissolving the compounds of Formula 1 or Formula 2 in an organicsolvent, for example, methanol, ethanol, acetone, methylene chloride,acetonitrile, etc. and then the precipitate formed by adding an organicand or inorganic acid is filtered and dried, or by distilling a solventand an excess acid under reduced pressure and then drying orrecrystallizing it in an organic solvent.

In addition, the pharmaceutically acceptable metal salts may be preparedwith bases. Alkali metal salts or alkaline earth metal salts are, forexample, obtained by dissolving a compound in an excess alkaline metalhydroxide or an alkaline earth metal hydroxide solution, filtering anundissolved compound salt and then evaporating and drying its filtrate.At this time, it is appropriate pharmaceutically to prepare sodium,potassium or calcium salts as metal salts. In addition, correspondingsilver salts may be obtained by reacting the alkali metal or alkalineearth metal salts with suitable silver salt (e.g., silver nitrate).

Furthermore, the present invention includes not only the compoundsexpressed in Formula 1 or Formula 2 and their pharmaceuticallyacceptable salts but also solvates, hydrates, isomers, etc. that can beprepared therefrom.

In addition, the present invention provides a method for preparation ofthe compounds expressed in Formula 1 or Formula 2 above, comprising thestep (step 1) as shown in Reaction Equation 1 below in which thecompound expressed in Formula 3 or Formula 4 and a compound expressed inFormula 5 are placed in a solvent with a reaction catalyst and thenstirred.

In Reaction Equation 1 above,

X^(a) is —OH or —NH₂, and

R¹, R², R³, R^(4a), R^(4b), R^(4c), R^(4d), R⁵, X and L are as definedin Formulae 1 and 2 above.

In the following is described a preparation method of the presentinvention in detail.

In the preparation method according to the present invention, dimethylformamide (DMF), methylene chloride (MC), ethanol, water, diisopropylether, diethyl ether, dioxane, tetrahydro furan (THF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), chlorobenzene, toluene,benzene and the like may be used independently or mixed and used for thesolvent.

In the preparation method according to the present invention,1-ethyl-3-(3-dimethyl amino propyl) carbodiimide) (EDCI), hydroxylbenzotriazole (HOBt), triethyl amine (TEA),0-(7-azobenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (HATU), pyridine, POCl₃, Fe, HCl and the like may be usedindependently or mixed and used, as the reaction catalyst.

In the preparation method according to the present invention, thereaction temperature of the step 1 is preferably 0-30° C., and thereaction time is preferably 1 hour to 2 days but is not limited to thistime.

Further, the present invention provides pharmaceutical compositions forprevention or treatment of viral diseases containing the compoundsexpressed in Formula 1 or Formula 2 above, pharmaceutically acceptablesalts thereof, or optical isomers thereof as active ingredients.

At this time, the viral diseases are diseases caused by picornavirusesincluding coxsackievirus, enterovirus, poliovirus and rhinovirus.Herein, the viral diseases may include infantile paralysis, acutehemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouthdisease, vesicular disease, hepatitis A, myositis, myocarditis,pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpanginaand food-and-mouth disease.

Since the compounds expressed in Formula 1 or Formula 2 that are inequilibrium states with each other according to the present inventionhave not only low cytotoxicity but also very excellent antiviralactivities against picornaviruses including coxsackievirus, enterovirus,poliovirus and rhinovirus, they can be used effectively aspharmaceutical compositions for prevention or treatment of viraldiseases including poliomyelitis, acute hemorrhagic conjunctivitis,viral meningitis, hand-foot-and-mouth disease, vesicular disease,hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemicmyalgia, encephalitis, flu, herpangina, foot-and-mouth disease, asthma,chronic obstructive pulmonary disease, pneumonia, sinusitis or otitismedia.

The compounds expressed in Formula 1 or Formula 2 according to thepresent invention may be administered in the form of variousformulations including oral and non-oral clinical administration, andare prepared for formulation using a typical diluent or excipient suchas filler, thickening agent, binder, wetting agent, disintegrant,surfactant, and the like.

Solid preparations intended for oral administration include tablets,pills, powders, granules, capsules and troches and such solidpreparations are prepared by mixing at least one compound of the presentinvention with at least one excipient, for example, starch, calciumcarbonate, sucrose, lactose, or gelatin. In addition to a simpleexcipient, a lubricant such as magnesium stearate and talc is also used.While liquid preparations for oral administration include suspensions,internal use solutions, emulsions, syrups and the like, in addition to asimple diluent commonly used such as water, liquid paraffin and thelike, various excipients may be included; for example, wetting agents,sweetening agents, aromatics, preservatives, and the like.

Preparations intended for non-oral administration include sterileaqueous solutions, non-aqueous solutions, suspensions, emulsions,lyophilization, suppositories and the like. Propylene glycol,polyethylene glycol, vegetable oils such as olive oil, and esters suchas injectable ethyl oleate may be used for the non-aqueous solvents andsuspensions. For suppository bases, witepsol, macrogol, tween 61, cacaobutter, laurin butter, glycerol, and gelatin may be used.

The compound of the present invention is administered in atherapeutically effective amount. The effective dose of the compound ofthe present invention varies depending on various factors including apatient's age, weight, sex, dosing method and health condition, and theseverity of disease. Typically, the compound of the present inventionmay be administered at a daily dose of from 0.001 to 100 mg/kg; andpreferably at a daily dose of from 0.01 to 35 mg/kg. For an adult with aweight of 70 kg, the dose of the compound of the present invention maytypically range from 0.07 to 7,000 mg/day, and preferably from 0.7 to2,500 mg/day. The formulations of the compound may be administered in asingle dose/day or may be divided into multiple doses at regularintervals of time according to the determination of a physician orpharmacist who is responsible for monitoring or observing theadministration of the drug.

Mode for Implementation of the Invention

In the following is described the present invention in further detailbased on the examples below. However, the examples below merelyillustrate the present invention, and details of the present inventionare not limited by the examples below.

EXAMPLE 1 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)-2-(1H-indol-3-yl)-2-oxoacetamide

After 2-(1H-indol-3-yl)-2-oxo acetic acid (352 mg, 1.86 mmol), EDCl(1-ethyl-3-(3-dimethyl amino propyl) carbodiimide) (355 mg, 1.86 mmol),and HOBt (hydroxyl benzotriazole) (251 mg, 1.86 mmol) are dissolved inmethylene chloride (MC) (10 ml), and9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo [d] indeno [1,2-b] furan-10(9bH)-one (500 mg, 1.69 mmol) is added and the mixture is stirred atnormal temperature for one day. The reaction mixture is extracted withmethylene chloride to collect an organic layer and the layer is driedunder MgSO₄ and concentrated under reduced pressure. The concentratedcompound is purified using silica gel column chromatography (ethylacetate: n-hexane=1:1) to obtain N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo [d] indeno [1,2-b]furan-9b-yl)-2-(1H-indo1-3-yl)-2-oxo acetamide (199 mg, 25%).

¹H-NMR (Acetone, 300 MHz) δ 1.18 (d, J=6.8 Hz, 6H, CH3), 2.87 (sep,J=6.8 Hz, 1H, CH), 6.72 (s, 1H, ArH), 6.93 (d, J=7.9 Hz, 1H, ArH),7.26-7.29 (m, 2H, ArH), 7.44 (d, J=7.8 Hz, 1H, ArH), 7.54-7.57 (m, 1H,ArH), 7.66-7.75 (m, 1H, ArH), 7.81-7.94 (m, 2H, ArH), 7.99-8.03 (m, 1H,ArH), 8.32-8.35 (m, 1H, ArH), 8.80 (s, 1H, ArH), 11.30 (br, 1H, NH);

466.93 [M+H]+, 933.23 [2M+H]+ for LCMS.

EXAMPLE 2 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-(thiopen-2-yl)acetamide

After 2-oxo-2-(thiopen-2-yl) acetic acid (107 mg, 1.07 mmol) isdissolved in DMF (3 ml), the temperature is lowered to 0° C. and thesolution is stirred. After 10 minutes, triethyl amine (TEA) (213 mg,1.07 mmol) and HATU (407 mg, 1.07 mmol) are added, and stirred for 10min before the temperature is lowered to 0° C. and9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (300 mg, 1.02 mmol) is added. Next, the temperature is raisedto normal temperature, and then the solution is stirred overnight. Afterwashing with water, moisture is removed with Na₂SO₄. After filtering andconcentration, purification is carried out with column chromatography(EA: Hex=3:7) to obtain the target compound (52 mg, 28%)

¹H-NMR (300 MHz, DMSO-d6) δ 1.12 (d, 6H, J=6.0 Hz), 4.13 (q, 1H, J=6.0Hz), 4.72 (s, 1H), 6.88 (d, 1H, J=6.0 Hz), 7.32 (d, 2H, J=6.0 Hz),7.63-7.67 (m, 1H), 7.76-7.78 (d−1H), 7.87-7.98 (m, 2H), 8.10 (s, 1H),8.19 (d, 1H, J=6.0 Hz), 8.56 (s, 1H), 9.56 (s, 1H);

433.75 [M+H]+, 866.87 [2M+H]+ for LCMS.

EXAMPLE 3 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-3-(2-nitro phenyl)-2-oxopropanamide

After 2-nitrophenyl pyruvic acid (390 mg, 1.86 mmol) is placed inDMF:DCM (1:2, 15 ml), EDCl (487 mg, 2.54 mmol) is added at 0° C. Next,after 1-hydroxy benzotriazole (343 mg, 2.54 mmol) is added, stirring iscarried out at room temperature for 15-30 minutes. Next, after9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (500 mg, 1.69 mmol) is added, TEA (0.709 ml, 5.09 mmol) isadded. After stirring at 60° C. for two days, water (100 ml) is added.After organic layers are separated with ethyl acetate (70 ml×3) they arecollected and washed with water (50 ml) and brine (50 ml), moisture isremoved with sodium sulfate. After concentration, purification iscarried out in a silica gel column chromatography (25% ethylacetate:hexane) to obtain the target compound 100 mg (24%).

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (dd, J=2.7 Hz, J=6.9 Hz, 6H, CH3), 2.84(sept, J=6.9 Hz, 1H, CH), 4.54 (dd, J=19 Hz, J=42 Hz, 2H, CH2), 6.73 (s,1H, ArH), 6.86 (d, J=7.5 Hz, 1H, ArH), 7.27-7.34 (m, 2H, ArH), 7.46-7.51(m, 1H, ArH), 7.55-7.62 (m, 2H, ArH), 7.80-7.84 (m, 3H, ArH), 7.51 (d,J=7.8 Hz, 1H, ArH), 8.15 (d, J=8.1 Hz, 1H, ArH);

LCMS: 486.90 (M+H)+.

EXAMPLE 4 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo propanamide

After adding 9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b]benzofuran-10 (9bH)-one (500 mg, 1.69 mmol) in anhydrous DCM (15 ml) andlowering the temperature to 0° C., pyridine (0.276 ml, 3.39 mmol) isadded. Then pyruvic acid (0.13 ml, 1,86 mmol) and POCl₃ (0.175 ml, 1.86mmol) are added in that order at 0° C. After stirring at roomtemperature, organic layers separated using water (100 ml) and DCM (100ml×2) are collected and washed with dil HCl (1N, 50 ml), water (50 ml)and brine (50 ml) in this order. After removing moisture with anhydroussodium sulfate and then concentrating, purification is carried out in aflash silica gel column chromatography (25% ethyl acetate in hexane) toobtain the white target compound 130 mg (21%).

¹H-NMR (300 MHz, CDCl₃) δ 1.18 (dd, J=3.9 Hz, J=6.9 Hz, 6H, CH3), 2.42(s, 3H, CH3), 2.83 (sept, J=6.9 Hz, 1H, CH), 4.93 (br, 1H, OH), 6.73 (s,1H, ArH), 6.85 (d, J=7.5 Hz, 1H, ArH), 7.29 (d, J=7.5 Hz, 1H, ArH),7.56-7.61 (m, 1H, ArH), 7.80-7.84 (m, 2H, ArH), 7.89 (br, 1H, NH), 7.99(d, J=8.4 Hz, 1H, ArH);

LCMS: 365.92 (M+H)+.

EXAMPLE 5 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo pentanamide

After adding 9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b]benzofuran-10 (9bH)-one (500 mg, 1.69 mmol) in anhydrous DCM (15 ml) andlowering the temperature to 0° C., pyridine (0.276 ml, 3.39 mmol) isadded. Then 2-oxa valeric acid (207 mg, 1.78 mmol) and POCl₃ (0.175 ml,1.86 mmol) are added in that order at 0° C. After stirring at roomtemperature for 15 hours, organic layers separated using water (100 ml)and DCM (100 ml×2) are collected and washed with dil HCl (1N, 50 ml),water (50 ml) and brine (50 ml) in this order. After removing moisturewith anhydrous sodium sulfate and them concentrating, purification iscarried out in a flash silica gel column chromatography (25% ethylacetate in hexane) to obtain the white target compound 240 mg (37%).

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (t, J=7.5 Hz, 3H, CH3), 1.18 (dd, J=2.7Hz, J=6.9 Hz, 6H, CH3), 1.59-1.69 (m, 2H, CH2), 2.75-2.88 (m, 3H,CH2+CH), 4.88 (br, 1H, OH), 6.73 (s, 1H, ArH), 6.85 (d, J=7.8 Hz, 1H,ArH), 7.28 (d, J=7.8 Hz, 1H, ArH), 7.56-7.61 (m, 1H, ArH), 7.81-7.85 (m,2H, ArH), 7.93 (br, 1H, NH), 8.00 (d, J=8.1 Hz, 1H, ArH);

LCMS: 393.97 (M+H)+.

EXAMPLE 6 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo octanamide

After 9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (500 mg, 1.69 mmol) is added in anhydrous DCM (15 ml), thetemperature is lowered to 0° C. After pyridine (0.296 ml, 3.39 mmol) isadded, 2-oxa octanoic acid (281 mg, 1.78 mmol) and POCl₃ (0.175 ml, 1.86mmol) are added in that order at 0° C. After stirring at roomtemperature for 15 hours, organic layers separated using water (100 ml)and DCM (100 ml×2) are collected and washed with dil HCl (1N, 50 ml),water (50 ml) and brine (50 ml) in this order. After removing moisturewith anhydrous sodium sulfate and them concentrating, purification iscarried out in a flash silica gel column chromatography (15% ethylacetate in hexane) to obtain the white target compound 140 mg (20%).

¹H-NMR (300 MHz, CDCl₃) δ 0.86 (t, J=7.2 Hz, 3H, CH3), 1.18 (dd, J=3.0Hz, J=6.9 Hz, 6H, CH3), 1.26-1.31 (m, 6H, CH2), 1.53-1.60 (m, 2H, CH2),2.77-2.88 (m, 3H, CH2+CH), 4.90 (br, 1H, OH), 6.73 (s, 1H, ArH), 6.85(d, J=7.8 Hz, 1H, ArH), 7.28 (d, J=7.8 Hz, 1H, ArH), 7.56-7.61 (m, 1H,ArH), 7.80-7.85 (m, 2H, ArH), 7.98 (br, 1H, NH), 8.00 (d, J=8.4 Hz, 1H,ArH);

LCMS: 435.97 (M+H)+.

EXAMPLE 7 Preparation of2-(furan-2-yl)-N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo acetamide

After 2-oxa-2-furyl acetic acid (237 mg, 1.69 mmol) is added in DMF:DCM(1:2, 15 ml), EDCl (487 mg, 2.54 mmol) is added at 0° C. After adding1-hydroxy benzotriazole (343 mg, 2.54 mmol), stirring is carried out atroom temperature for 15-30 min. After adding9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (500 mg, 1.69 mmol), stirring is carried out at roomtemperature for two days. Organic layers separated using water (100 ml)and ethyl acetate (70 ml×3) are collected and then washed with water (50ml) and brine (50 ml) in that order. After removing moisture withanhydrous sodium sulfate and then concentrating, purification is carriedout in a flash silica gel column chromatography (25% ethylacetate:hexane) to obtain the target compound 40 mg (6%).

¹H-NMR (300 MHz, CDCl₃) δ1.18 (d, J=6.9 Hz, 6H, CH3), 2.84 (sept, J=6.9Hz, 1H, CH), 4.91 (br, 1H, OH), 6.57-6.59 (m, 1H, ArH), 6.75 (s, 1H,ArH), 6.86 (d, J=7.8 Hz, 1H, ArH), 7.33 (d, J=7.8 Hz, 1H, ArH),7.57-7.62 (m, 1H, ArH), 7.76 (m, 1H, ArH), 7.81-7.87 (m, 2H, ArH),8.00-8.06 (m, 2H, ArH), 8,23 (br, 1H, NH);

LCMS: 417.90 (M+H)+.

EXAMPLE 8 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indol-3-yl)-2-oxoacetamide

After 3-indol glyoxalic acid (195 mg, 1.03 mmol) is placed in DMF:DCM(1:2, 10 ml), EDCl (296 mg, 1.54 mmol) is added at 0° C.

After 1-hydroxy benzotriazole (205 mg, 1.54 mmol) is added, stirring iscarried out at room temperature for 15-30 min. After9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (300 mg, 1.03 mmol) is added, stirring is carried out at roomtemperature overnight. Organic layers separated using water (100 ml) andethyl acetate (70 ml×3) are collected and then washed with water (50 ml)and brine (50 ml) in that order. After removing moisture with anhydroussodium sulfate and then concentrating, purification is carried out in aflash silica gel column chromatography (25%, ethyl acetate: hexane) toobtain the white target compound (100 mg, 20%).

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (dd, J=4.5 Hz, J=6.9 Hz, 6H), 2.86 (sept,J=6.9 Hz, 1H), 6.71 (s, 1H), 6.94 (d, J=8.1 Hz, 1H, ArH), 7.26-7.49 (m,5H), 8.00-8.17 (m, 4H, ArH), 8.68 (s, 1H), 9.16 (s, 1H);

LCMS: 511.86 (M+H)+.

EXAMPLE 9 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-3-(4-hydroxy phenyl)-2-oxopropanamide

After 3-(4-hydroxy phenyl)-2-oxo propanoic acid (97 mg, 0.54 mmol) isdissolved in DMF (3 ml), the temperature is lowered to 0° C. andstirring is carried out. After 10 min, triethyl amine (TEA) (78 mg, 0.77mmol) and HATU (205 mg, 0.54 mmol) are added. After stirring for 10 min,the temperature is lowered to 0° C.,9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (150 mg, 0.51 mmol) is added. The temperature is raised tonormal temperature, and stirring is carried out overnight. After rinsingwith water, moisture is removed with Na₂SO₄, and filtering andconcentration is carried out, purification is carried out in a columnchromatography (EA:Hex =3:7) to obtain the target compound (14 mg, 6%).

¹H-NMR (300 MHz, CDCls) δ 1.17 (d, 6H, J=6.0 Hz), 2.73-2.90 (m, 1H),3.98-4.07 (m, 2H), 6.68-6.86 (m, 5H), 7.04 (d, 2H, J=6.0 Hz)7.52-7.59(m, 2H), 7.80-7.86 (m, 2H), 7.97-8.00 (d, 1H, J=9.0 Hz);

457.83 [M+H]+, 915.14 [2M+H]+ for LCMS

EXAMPLE 10 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indo1-3-yl)-2-oxoacetamide

After b-hydroxy-7-isopropyl-4-nitro-10-oxo-7b, 10-dihydro-4bH-indemo[1,2-b] benzofuran-9b-yl)-2-(1H-inolo1-3-yl)-2-oxo acetamide (70 mg,0.14 mmol) is placed in ethanol:water (10:1, 10 ml:1 ml), the mixture isheated to 60° C. After adding iron (23 mg, 0.41 mmol) and two drops ofconc. HCl, heating and refluxing is carried out for 3 hours. After thederived compound is filtered in a celite bed at high temperature, theliquid is washed with ethyl acetate (15 ml×2) and then concentratedbefore ethyl acetate (100 ml) is added.

After washing with sat. NaHCO₃ (20 ml), water (20 ml) and brine (20 ml)in that order, moisture is removed with anhydrous sodium sulfate. Afterconcentration and drying, a small amount of DCM is added and thenultrasonic waves are applied. The solid compound formed at this time isfiltered to obtain the yellow target compound (50 mg, 75%).

¹H-NMR (300 MHz, CD₃OD) δ 1.19 (d, J=6.9 Hz, 6H, CH3), 2.85 (sept, J=6.9Hz, 1H, CH), 6.67-6.73 (m, 2H, ArH), 6.90 (m, 1H, ArH), 7.03 (m, 1H,ArH), 7:25 (m, 2H, ArH), 7.45 (m, 3H, ArH), 8.29 (m, 1H, ArH), 8.64 (m,1H, ArH);

LCMS: 481.90 (M+H)+.

EXAMPLE 11 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl acetamide

After N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-9b, 10-dihydro-4bH-indeno[1,2-b] benzofuran-9b-yl)-2-oxo-phenyl acetamide (100 mg, 0.21 mmol) isadded in ethanol:water (10:1, 10 ml:1 ml), the mixture is heated to 60°C. After iron (36 mg, 0.64 mmol) and two drops of conc. HCl are added,refluxing is carried out by heating for 2 hours. After the derivedcompound is filtered on a celite bed at high temperature, the liquid iswashed with ethyl acetate (15 ml×2) and then concentrated before ethylacetate (100 ml) is added. After washing it with sat. NaHCO₃ (20 ml),water (20 ml) and brine (20 ml) in that order, moisture is removed withanhydrous sodium sulfate. After concentration and drying, a small amountof DCM is added and then ultrasonic waves are applied. The solidcompound formed at this time is filtered to obtain the yellow targetcompound (90 mg, 90%).

¹H-NMR (300 MHz, CD₃OD) δ 1.17 (d, J−6.9 Hz, 6H, CH3), 2.83 (sept, J=6.9Hz, 1H, CH), 6.67-6.71 (m, 2H, ArH), 6.87 (d, J=7.5 Hz, 1H, ArH), 7.03(d, J=7.5 Hz, 1H, ArH), 7.31-7.55 (m, 4H, ArH), 7.64-7.69 (m, 1H, ArH),8.08-8.16 (m, 2H, ArH);

LCMS: 442.92 (M+H)+.

EXAMPLE 12 Preparation of N-(4b-hydroxy-7, 8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl acetamide

After dissolving 2-oxo-2-phenyl acetate (281 mg, 1.0 mmol) in DCM (10.0ml), the temperature is lowered to 0° C. After EDCl (230 mg, 1.2 mmol)is placed at 0° C., stirring is carried out for 10 min. After addingHOBt (162 mg, 1.2 mmol) at 0° C. and then stirring for 10 min,9b-amino-4b-hydroxy-7.8-dimethyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (281 mg, 1.0 mol) is added at 0° C. and then stirring iscarried out at room temperature for 12 hours. After washing with water,removing moisture with Na₂SO₄, concentrating under reduced pressure, andpurifying in a column, the target compound (219 mg, 53%) is obtained.

¹H-NMR (300 MHz, CDCl₃) δ 2.17 (s, 3H), 2.19 (s, 3H), 4.87 (s, 1H), 6.68(s, 1H), 7.18 (s, 1H), 7.42-7.47 (m, 2H), 7.55-7.64 (m, 2H), 7.80-7.85(m, 2H), 8.01 (d, J=7.56 Hz, 1H), 8.11 (s, 1H) 8.26 (s, 1H), 8.29 (s,1H);

413.86 [M+H]+, 826.98 [2M+H]+ for LCMS.

EXAMPLE 13 Preparation of N-(4b-hydroxy-7,8-dimethyl -10-oxo-9b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-(1H-indo1-3-yl)-2-oxoacetamide

After dissolving 2-(1H-indo1-3-yl)-2-oxo acetic acid (209 mg, 1.1 mmol)in DCM (10.0 ml), the temperature is lowered to 0° C. After EDCl (230mg, 1.2 mmol) is placed at 0° C., stirring is carried out for 10 min.After adding HOBt (162 mg, 1.2 mmol) at 0° C. and then stirring for 10min, 9b-amino-4b-hydroxy-7.8-dimethyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (281 mg, 1.0 mol) is added at 0° C. and then stirring iscarried out at room temperature for 12 hours. After washing with water,removing moisture with Na₂SO₄, concentrating under reduced pressure, andpurifying in a column, the target compound (194 mg, 43%) is obtained.

¹H-NMR (300 MHz, CDCl₃) δ 2.14 (s, 3H), 2.17 (s, 3H), 5.23 (br s, 1H),6.69 (s, 1H), 7.17 (s, 1H), 7.33 (s, 1H), 7.42 (s, 1H), 7.52-7.94 (m,4H), 8.40 (s, 1H), 8.53 (s, 1H), 8.87 (s, 2H);

452.83 [M+H]+, 904.95 [2M+H]+ for LCMS.

EXAMPLE 14 Preparation of N-(4b-hydroxy-7, 8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo propanamide

After adding 9b-amino-4b-hydroxy-7, 8-dimethyl-4bH-indeno [1,2-b]benzofuran-10 (9bH)-one (300 mg, 1.07 mmol) in DCM (20 ml), thetemperature is lowered to 0° C. After adding pyridine (168 mg, 2.13mmol) and stirring for 10 min, 2-oxo propanoic acid (94 mg, 1.07 mmol)is added. After adding POCl₃ (0.1 ml, 1.07 mmol) in a stirred state,stirring is carried out at room temperature for 15 hours. After anorganic layer is separated using DCM (100 ml) and H₂O (100 ml), washingis carried out with 1N HCl and NaCl in that order, moisture is removedwith Na₂SO₄ and concentration is carried out. Next, purification iscarried out in a column to obtain the target compound (56 mg, 15%).

¹H-NMR (300 MHz−CDCl₃) δ 2.16 (s, 3H), 2.18 (s, 3H), 2.44 (s, 3H), 4.86(br s, 1H), 6.66 (s, 1H), 7.12 (s, 1H), 7.57 (t, J=7.2 Hz, 1H),7.79-7.82 (m, 2H), 7.92-8.00 (m, 2H);

351.83 [M+H]+, 702.84 [2M+H]+ for LCMS.

EXAMPLE 15 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl acetamide

After dissolving phenyl glyoxylic acid (0.30 g, 2.03 mmol) in anhydrousmethylene chloride (10 ml), EDCl (0.38 g, 2.03 mmol), HOBt (0.27 g, 2.03mmol), 3-(2-amino ethyl)-9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno[1,2-b] benzofuran-10 (9bH)-one (0.50 g, 1.69 mmol) and triethyl amine(0.25 g, 2.53 mmol) are added and stirring is carried out at roomtemperature for 24 hours. After diluting with methylene chloride andwashing with water several times, the organic layer is dried andfiltered. After purifying in a column chromatography (ethylacetate:hexane=1:2), the target compound (0.20 g, 27%) is obtained.

¹H-NMR (300 MHz, CDCl₃) δ 1.16-1.19(dd, J=6.9, 3.0 Hz, 2H, CH2)2.77-2.89(m, 1H, CH) 4.93(s, 1H, OH) 6.75(s, 1H, NH) 6.87(d, J=7.8 Hz,1H, ArH) 7.44(t, J=8.1 Hz, 2H, ArH) 7.57-7.64(m, 3H, ArH) 7.85(m, 1H,ArH) 8.02(d, J=7.5 Hz, 1H, ArH) 8.09(s, 1H, ArH). 8.26(d, J=7.2 Hz, 2H,ArH);

MS (El) m/e (rel·intensity) 428(M+H)+, 855(2M+H)+ for LCMS.

EXAMPLE 16 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenyl acetamide

After adding phenyl glyoxalic acid (155 mg, 1.03 mmol) in DMF:DCM (1:210 ml), EDCl (296 mg, 1.54 mmol) is added at 0° C. After adding1-hydroxy benzotrinaole (205 mg, 1.54 mmol), stirring is carried out atroom temperature for 15-30 min. After adding9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (300 mg, 1.03 mmol), stirring is carried out at roomtemperature overnight. The organic layers separated using water (100 ml)and ethyl acetate (70 ml×3) are collected and washed with water (50 ml)and brine (50 ml) in that order. After removing moisture with anhydroussodium sulfate and then concentrating, purification is carried out in aflash silica gel column chromatography (25% ethyl acetate hexane) toobtain the target compound (125 mg, 30%).

¹H-NMR (300 MHz, CDCl₃) δ 1.19 (dd, J=3.3 Hz, J=6.9 Hz, 6H, CH3), 2.86(sept, J=6.9 Hz, 1H, CH), 6.50 (s, 1H, OH), 6.73 (s, 1H, ArH), 6.94 (d,J=7.8 Hz, 1H, ArH), 7.41-7.49 (m, 3H, ArH), 7.58-7.63 (m, 2H, ArH+NH),7.77-7.82 (m, 1H, ArH), 8.26-8.29 (m, 3H, ArH), 8.50 (dd, J=8.1 Hz, J=1Hz, 1H, ArH);

LCMS: 472.80 (M+H)+.

EXAMPLE 17 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-4-(methyl thio)-2-oxobutanamide

9b-amino-4b-hydroxy-7-isopropyl-4bH-indeno [1,2-b] benzofuran-10(9bH)-one (500 mg, 1.7 mmol) and pyridine (269 mg, 3.4 mmol) aredissolved in DCM. After adding POCl₃ (286 mg, 1.87 mmol) and then4-(methylthio)-2-oxo butanoic acid sodium salt (318 mg, 1.87 mmol),stirring is carried out at normal temperature overnight. After washingwith water, moisture is removed with Na₂SO₄, and filtration andconcentration is carried out, purification is performed in a columnchromatography (EA:Hex=3:7) to obtain the target compound (50 mg, 7%).

¹H-NMR (300 MHz, DMSO-d6) δ 1.12 (d, 6H, J=6.0 Hz), 2.53 (s, 3H),2.78-2.85 (m, 2H), 3.00-3.15 (m, 3H), 6.70 (s, 1H), 6.87 (d, 1H, J=6.0Hz), 7.28 (d, 1H, J=9.0 Hz), 7.61-7.65 (m, 1H), 7.73 (d, 1H, J=6.0 Hz),7.87-7.91 (m, 2H).

EXAMPLE 18 Preparation of 4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl propyl carbamate

After dissolving 9b-hydroxy-7-isopropyl-4b-methoxy-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (300 mg, 1.0 mmol) inDCM (20 ml), stirring is carried out at 0° C. After dissolvingTriphosgene (phosgene) (300 mg, 1.00 mmol) in TEA (0.14 mL, 1.10 mmol),it is added at 0° C. After dissolving the reaction for 10 min andconcentrating under reduced pressure, any remaining phosgene is removed.After verifying that the starting material has disappeared using TLC,n-propyl amine (0.05 ml, 2 eq.) and TEA (2 eq.) are added in DCM (20 ml)and dissolved prior to addition. After reacting at normal temperaturefor 12 hours, the reactants are concentrated upon completion of thereaction and then purification is carried out in a silica gelchromatography (20% EA in Hex) to obtain the target compound (106 mg,83%).

¹H-NMR (300 MHz, CDCl3) δ 0.71 (t, J=7.5 Hz, 3H), 1.18 (dd, J=6.9 Hz,J=3.0 Hz, 6H), 1.38-1.54 (m, 2H), 2.85 (septet J=6.9 Hz, 1H), 3.32-3.37(m, 2H), 3.89 (s, 1H), 4.47 (s, 1H), 6.73 (s, 1H), 6.87 (d, J=7.8 Hz,1H), 7.47-7.66 (m, 4H), 7.79 (d, J=7.8 Hz, 1H);

382.29 [M+H]+, 763.96 [2M+H]+ for LCMS.

EXAMPLE 19 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo propanamide

After dissolving 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (464 mg, 1.136 mmol) inanhydrous THF (50 ml, 0.02 M), TEA (0.396 ml, 2.839 mmol) is added whilestirring slowly. Next, pyruvic acid (100 mg, 1.136 mmol) is added at 10°C. Phosphorous oxy chloride (106 mL, 1,136) is added slowly drop bydrop. After reacting at normal temperature for 5 hours, extraction iscarried out with ethyl acetate (EA) upon completion of the reaction,washing is carried out with water, water is removed with Na₂SO₄, and thereactants are concentrated. Next, purification is performed in a silicagel chromatography (15% EA in Hex) to obtain the target compound (70 mg,15%) and to recover 100 mg of the starting material.

¹H-NMR (300 MHz, CDCl3) δ 1.18 (dd, J=6.9 Hz, J=3.0 Hz 6H), 2.43 (s,3H), 2.85 (sept, J=6.9 Hz, 1H), 6.46 (s, 1H), 6.71 (s, 1H), 6.93 (d,J=7.8 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.76-7.81 (m, 1H), 8.24 (d, J=7.2Hz, 1H), 8.50 (d, J=7.8 Hz, 1H);

410.82 [M+H]+, 820.82 [2M+H]+ for LCMS.

EXAMPLE 20 Preparation of N1-(2,6-dimethylphenyl)-N2-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)oxal amide

After dissolving 2-((2,6-dimethyl phenyl) amino)-2-oxo acetic acid (240mg, 1.24 mmol) is dissolved in DCM (20 ml), EDCl (357 mg, 1.86 mmol) isadded at 0° C. while stirring and 1-hydroxy benzotriazole (252 mg, 1.86mmol) is also added. While stirring, 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (404 mg, 1.37 mmol) isadded, and then the reaction is carried out at normal temperature for 24hours by adding TEA (0.258 ml, 1.86 mmol) drop by drop. Upon completionof the reaction, water (100 ml) and ethyl acetate (70 ml×2) are used forextraction and then washing is carried out once more with brine (50 ml).After removing water with Na₂SO₄, the mixture obtained by concentrationunder pressure is purified in a silica gel column chromatography (15-20%EA in Hex) to obtain the target compound (360 mg, 62%).

¹H-NMR (300 MHz, CD30D) δ 1.16 (d, J=6.9 Hz, 6H), 2.19 (s, 6H), 2.83(sept, J=6.9 Hz, 1H), 6.68 (s, 1H), 6.90 (d, J=7.2 Hz, 1H), 7.09 (br,3H), 7.42 (d, J=7.2 Hz, 1H), 7.65-7.90 (br, 4H);

471.29 [M+H]+ for LCMS.

EXAMPLE 21 Preparation of N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2, N2-dimethyl oxal amide

After dissolving 2-(dimethyl amino)-2-oxo acetic acid (200 mg, 1.71mmol) in DCM (20 ml), EDCl (654 mg, 3.41 mmol) is added at 0° C. whilestirring, and 1-hydroxy benzotriazole (346 mg, 2.56 mmol) is added.While stirring, 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (605 mg, 2.05 mmol) isadded, and then the reaction is carried out at normal temperature for 48hours by adding TEA (0.357 ml, 2.56 mmol) drop by drop. Upon completionof the reaction, water (100 ml) and ethyl acetate (70 ml×2) are used toextract and then washing is carried out once more with brine (50 ml).After removing water with Na₂SO₄, the mixture obtained by concentrationunder pressure is purified in a silica gel column chromatography (50% EAin Hex) to obtain the target compound (450 mg, 67%).

¹H-NMR (300 MHz, CD30D) δ 1.16 (d, J=6.9 Hz, 6H), 2.82 (sept, J=6.9 Hz,1H), 2.95 (s, 3H), 3.16 (s, 3H), 6.67 (s, 1H), 6.87 (d, J=7.8 Hz, 1H),7.37 (d, J=7.8 Hz, 1H), 7.62-7.90 (br, 4H);

394.98 [M+H]+, 789.09 [2M+H]+ for LCMS.

EXAMPLE 22 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo propanamide

After dissolving N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno [1,2-b] benzofuran-9b-yl)-2-oxo propanamide (200mg, 0.49 mmol) in ethanol:water (10:1, 10 ml), iron (82 mg, 1.46 mmol)is added. After adding conc. HCl (2 drops) and reacting at 90° C. for 2hours, filtration is carried out with celite under high temperature uponcompletion of the reaction and then washing is carried out with ethylacetate. After extracting with DCM and washing with water, washing iscarried out with brine (50 ml) again. Water is removed with Na₂SO₄ andthe reactants are concentrated before purification is carried out in asilica gel column chromatography (33% EA in Hex) to obtain the targetcompound (70 mg, 38%).

¹H-NMR (300 MHz, CD30D) δ 1.18 (d, J=6.9 Hz, 6H), 2.34 (s, 3H), 2.83(sept, J=6.9 Hz, 1H), 6.66-6.70 (m, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.98(d, J=8.4 Hz, 1H), 7.34-7.45 (m, 2H);

380.96 [M+H]+ for LCMS.

EXAMPLE 23 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-(3, 4,5-trimethoxy phenyl)acetamide

After 2-oxo-2-(3,4,5-trimethoxy phenyl) acetic acid (25 mg, 0.10 mmol)is dissolved in DCM (1 ml), HATU (59.4 mg, 0.16 mmol) and DIPEA (0.028ml, 0.16 mmol) are added in sequence while stirring at 0° C. Afterapproximately 5 min, 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (34 mg, 0.11 mmol) isadded and reaction is carried out for 12 hours. Upon completion of thereaction, DCM (50 ml×2) and water are used for extraction and washing iscarried out with brine. After removing water with Na₂SO₄ and thenconcentrating under reduced pressure, purification is carried out in asilica gel column chromatography (40% EA in Hex) to obtain the targetcompound (50 mg, 93%).

¹H-NMR (300 MHz, CD30D) δ 1.15 (dd, J=6.9 Hz, J=1.8 Hz, 6H), 2.81 (sept,J=6.9 Hz, 1H), 3.85 (s, 3H), 3.91 (s, 6H), 6.68 (s, 1H), 6.87 (d, J=7.8Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.50 (s, 2H), 7.57-7.62 (m, 1H),7.79-7.90 (m, 3H), 7.99 (d, J=7.8 Hz, 1H);

517.85 [M+H]+ for LCMS.

EXAMPLE 24 Preparation of (E)-4-(3, 4-dimethoxyphenyl)-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxobut-3-enamide

After dissolving (E)-4-(3,4-dimethoxy phenyl)-2-oxobut-3-enoic acid (25mg, 0.11 mmol) in DCM (1 ml), HATU (61 mg, 0.16 mmol) and DIPEA (0.028ml, 0.16 mmol) is added in that order while stirring at 0° C.

After approximately 5 min, 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (35 mg, 0.12 mmol) isadded and then reaction is carried out for 12 hours. Upon completion ofthe reaction, DCM (50 ml×2) and water are used for extraction andwashing is carried out with brine. After removing water with Na₂SO₄ andthen concentrating under reduced pressure, purification is carried outin a silica gel column chromatography (40% EA in Hex) to obtain thetarget compound (40 mg, 74%).

¹H-NMR (300 MHz, CD30D) δ 1.16 (d, J=6.9 Hz, 6H), 2.83 (sept, J=6.9 Hz,1H), 3.84 (s, 3H), 3.86 (s, 3H), 6.68 (s, 1H), 6.90 (d, J=7.8 Hz, 1H),6.98 (d, J=7.8 Hz, 1H), 7.25 (br, 3H) 7.31 (s, 1H), 7.41 (d, J=7.8 Hz,1H), 7.59-7.64 (m, 1H), 7.79-7.98 (m, 4H);

513.87 [M+H]+ for LCMS.

EXAMPLE 25 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-(2-nitro phenyl)-2-oxopropanamide

3-(2-nitrophenyl)-2-oxo propionic acid (185 mg, 0.88 mmol) is dissolvedin DCM (20 ml, 0.044 M). After stirring at 0° C. for 10 min, HATU (502.8mg, 1.32 mmol) and DIPEA (171 mg, 1.32 mmol) are added. After stirringat 0° C. for 10 min, 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (300 mg, 0.88 mmol) isadded and then stirring is carried out at normal temperature for 18hours. After extracting with ethyl acetate (EA) and washing with water,the reactant is concentrated and purification is carried out in a silicagel column chromatography (50% EA in Hex) to obtain the target compound(250 mg, 53%).

¹H-NMR (300 MHz, CDC13): δ 1.16-1.19 (m, 6H), 2.80-2.89 (m, 1H),4.48-4.70 (m, 2H), 6.49 (s, 1H), 6.72 (s, 1H), 6.93 (d, J=9.0 Hz, 1H),7.30 (d, J=9.0 Hz, 1H), 7.39-7.53 (m, 3H), 7.62 (t, J=9.0 Hz, 1H), 7.80(t, J=9.0 Hz, 1H), 8.18 (d, ]=9.0 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.52(d, J=9.0 Hz, 1H);

531.88 [M+H]+ for LCMS.

EXAMPLE 26 Preparation of N1-(2,6-dimethylphenyl)-N2-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)oxal amide

2-((2, 6-dimethyl phenyl) amino)-2-oxo acetic acid (170 mg, 0.88 mmol)is dissolved in DCM (20 ml, 0.044 M). After stirring at 0° C. for 10min, EDCl (253.5 mg, 1.32 mmol) and Hobt (133.8 mg, 1.32 mmol) areadded. After stirring at 0° C. for 10 min, TEA (178.6 mg, 1.32 mmol) and9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (300 mg, 0.88 mmol) is added prior to stirringat normal temperature for 18 hours. After extracting with ethyl acetate(EA) and washing with water, the reactants are concentrated and purifiedon silica gel column chromatography to obtain the target compound (90mg, 20%).

¹H-NMR (300 MHz, CDC13): δ 1.17-1.20 (m, 6H), 2.23 (s, 6H) 2.82-2.91 (m,1H), 6.49 (s, 1H), 6.73 (S, 1H), 6.93-6.95 (m, 1H), 7.08-7.14 (m, 3H),7.48-7.50 (d, J=6.0 Hz, 1H), 7.81 (t, J=9.0 Hz 1H), 7.95 (s, 1H),8.27-8.29 (d, J=6.0 Hz, 1H), 8.51-8.53 (m, 2H);

515.97 [M+H]+ for LCMS.

EXAMPLE 27 Preparation of N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-methyl oxal amide

Mono-(N-methyl)-amide oxalate (104.7 mg, 1.02 mmol) is dissolved in DCM(6 ml, 0.1 M). After stirring at 0° C. for 10 min, HATU (386.2 mg, 1.02mmol) and DIPEA (131 mg, 1.02 mmol) are added. After stirring at 0° C.for 10 min, 9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (200 mg, 0.68 mmol) is added prior to stirringat normal temperature for 18 hours. After stirring further at 50° C. for3 hours, DMF (6 ml) is added and stirring is carried out again for 1hour. After extracting with ethyl acetate (EA) and washing with water,the reactants are concentrated and purified on silica gel columnchromatography (50% EA in Hex) to obtain the target compound (37 mg,24%).

¹H-NMR (500 MHz, DMSO-d6): δ 1.13 (d, J=7 Hz, 6H), 2.66 (d, J=500 Hz,3H), 2.79-2.84 (m, 1H), 6.70 (s, 1H), 6.88 (d, J=8 Hz, 1H), 7.27-7.34(m, 1H), 7.56-7.98 (m, 4H), 8.20-8.30 (m, 1H), 8.46-8.54 (m, 1H),8.66-8.67 (m, 1H);

380.82 [M+H]+ for LCMS.

EXAMPLE 28 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3 methyl-2-oxo pentanamide

After adding and dissolving sodium salt 3-methyl-2-oxo pentanoic acid(300 mgl) is 1N HCl, stirring is carried out for 5 min, extraction iscarried out with ethyl acetate, and concentration is carried out underreduced pressure to obtain 3-methyl-2-oxo pentanoic acid (180 mg, 1.38mmol) which is dissolved in THF (0.1 M, 14 ml). Next,9b-amino-4b-hydroxy-7-isopropyl-1-nitro-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (517 mg, 1.52 mmol) is added, and whilestirring is carried out at −10° C. for 15 min, POCl₃ (14.0 ml, (0.2 M inTHF), 2.76 mmol) is slowly added with a syringe pump for 15 min andstirring is carried out. After adding POCl₃, the reaction is carried outat normal temperature for 2 hours, and upon completion of the reaction,concentration is carried out under reduced pressured. EA and water isused to carry out extraction, and the organic layer is washed with waterand brine before removing water with Na₂SO₄ and concentrating underreduced pressure. Finally, a column filled with silica is used to carryout purification before the target compound (90 mg, 15%) is obtained.

¹H-NMR (300 MHz, CDC 13): δ 0.84-0.94 (m, 3H), 1.07-1.13 (m, 3H),1.17-1.21 (m, 6H), 1.30-1.46 (m, 1H), 1.65-1.79 (m, 1H), 2.81-2.90 (m,1H), 3.31-3.41 (m, 1H), 6.71 (s, 1H), 6.93 (d, J=7.9 Hz, 1H), 7.43 (t,J=7.9 Hz, J=10.2 Hz, 2H), 7.75-7.81 (m, 1H), 8.25 (d, J=7.7 Hz, 1H),8.49 (d, J=8.0 Hz, 1H);

453.46 [M+H]+ for LCMS.

EXAMPLE 29 Preparation of N-(4b-hydroxy-7-isopryl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-2-oxo pentanamide

After adding and dissolving sodium salt 3-methyl-2-oxo pentanoic acid(300 mgl) is 1N HCl, stirring is carried out for 5 min, extraction iscarried out with ethyl acetate, and concentration is carried out underreduced pressure to obtain 3-methyl-2-oxo pentanoic acid (180 mg, 1.38mmol) which is dissolved in THF (0.1 M, 14 ml). Next,9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (450 mg, 1.52 mmol) is added, and while stirring iscarried out at −10° C. for 15 min, POCl₃ (14.0 ml, (0.2 M in THF), 2.76mmol) is slowly added with a syringe pump for 15 min and stirring iscarried out. After adding POCl₃, the reaction is carried out at normaltemperature for 2 hours, and upon completion of the reaction,concentration is carried out under reduced pressured. EA and water isused to carry out extraction, and the organic layer is washed with waterand brine before removing water with Na₂SO₄ and concentrating underreduced pressure. Finally, a column filled with silica is used to carryout purification before the target compound (190 mg, 30%) is obtained.

¹H-NMR (300 MHz, CDC13): δ 0.82-0.92 (m, 3H), 1.04-1.11 (m 3H),1.16-1.25 (m, 6H), 1.31-1.42 (m, 1H), 1.63-1.77 (m, 1H), 2.79-2.88 (m,1H), 3.33-3.39 (m, 1H), 6.84-6.87 (m, 1H), 7.28-7.31 (m, 1H), 7.56-7.61(m, 1H), 7.80-7.85 (m, 2H), 7.90-7.93 (m, 1H), 8.00 (d, J=7.8 Hz, 1H);

407.97 [M+H]+ for LCMS.

EXAMPLE 30 Preparation of N1-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-N2-dimethyl oxal amide

While 2-(dimethyl amino)-2-oxo acetic acid (180 mg, 1.54 mmol) is addedin DCM (0.1 M, 15.0 ml) at 0° C. and stirred, HATU (878 mg, 2.31 mmol)is added and the DIPEA (0.4 ml, 2.31 mmol) is added before stirring iscarried out. Finally, 9b-amino-4b-hydroxy-7-isopropyl-1-nitro-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (500 mg, 1.69 mmol) isadded and then stirring is carried out at normal temperature for 12hours. Upon completion of the reaction, water and DCM is used forextraction, washing is carried out with water again, and water isremoved with Na₂SO₄ before concentration is carried out under reducedpressure. Finally, a column filled with silica is used to carry outpurification before the target compound (550 mg, 81%) is obtained.

¹H-NMR (300 MHz, CDC13): δ 1.17-1.19 (m, 6H), 1.30-1.46 (m, 1H),2.81-2.87 (m, 1H), 3.02 (s, 3H), 3.34 (s, 3H), 6.70 (s, 1H), 6.91 (d,J=7.7 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.75-7.81 (m, 1H), 8.24 (d, J=8.0Hz, 1H), 8.49 (d, J=8.0 Hz, 1H);

439.88 [M+H]+ for LCMS.

EXAMPLE 31 Preparation of N1-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2, N2-dimethyl oxal amide

After dissolving N1-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno [1,2-b] benzofuran-9b-yl)-N2, N2-dimethyl oxalamide (200 mg, 0.46 mmol) is dissolved in EtOH:H2O (10:1) (0.02 M, 23.0ml), iron powder (77 mg, 1.38 mmol) is added. While stirring, conc. HCl(3 drops) is slowly added and the reaction is allowed to take placed at120° C. for 1.5 hours. Upon completion of the reaction, cooling iscarried out to normal temperature, concentration under reduced pressureis carried out, water and ethyl acetate is used for extraction, andwashing with water is carried out again before water is removed withNa₂SO₄ and then concentration is carried out under reduced pressure.Finally, a column filled with silica is used for purification to obtainthe target compound (75 mg, 40%).

¹H-NMR (300 MHz, CD30D): δ 1.17 (d, J=6.3 Hz, 6H), 2.78-2.87 (m, 1H),2.94. (s, 3H), 3.16 (s, 3H), 6.65-6.72 (m, 2H), 6.83-6.86 (m, 1H),6.98-7.00 (m, 1H), 7.35-7.37 (m, 1H), 7.42-7.47 (m, 1H);

409.94 [M+H]+ for LCMS.

EXAMPLE 32 Preparation of Ethyl 2-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) amino)-2-oxo acetate

9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (0.5 g, 1.69 mmol) is dissolved in THF (17 ml, 0.10mmol). TEA (0.36 ml, 2.54 mmol) and ethyl-2-chloro-2-oxo acetate (0.17ml, 1.52 mmol) are slowly added at −10° C. After stirring for 12 hours,THF is concentrated. After adding DCM, washing is carried out with waterand brine. After adding Na₂SO₄ and filtration, concentration is carriedout. A column filled with silica is used for purification to obtain thetarget compound (400 mg, 60%).

¹H-NMR (300 MHz, CDC13) δ 1.16-1.39 (m, 9H), 2.78-2.87 (m, 1H),4.31-4.39 (m, 2H).4.91 (br, 1H), 6.73 (s, 1H), 6.84 (d, J=8.1 Hz, 1H),7.29 (d, J=8.1 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.80-7.93 (m, 2H), 7.80(d, J=8.1 Hz, 1H), 8.11 (br, 1H);

396.24 [M+H]+ for LCMS.

EXAMPLE 33 Preparation of Ethyl2-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) amino)-2-oxo acetate

9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (0.5 g, 1.47 mmol) is dissolved in THF (15 ml, 0.10mmol). TEA (0.31 ml, 2.21 mmol) and ethyl-2-chloro-2-oxo acetate (0.15ml, 1.32 mmol) are slowly added at −10° C. After stirring for 12 hours,THF is concentrated. After adding DCM, washing is carried out with waterand brine. After adding Na₂SO₄ and filtration, concentration is carriedout. A column filled with silica is used for purification to obtain thetarget compound (240 mg, 60%).

¹H-NMR (300 MHz, CDC13) δ 1.17-1.22 (m, 6H), 1.36 (t, J=7.2 Hz, 3H),2.79-2.90 (m, 1H), 4.30-4.37 (m, 2H), 6.44-6.53 (m, 1H), 0.71 (br, 1H),6.93 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.54 (br, 1H), 7.77 (t,J=7.8 Hz, 1H), 8.21 (d, J=6.6 Hz, 1H), 8.48 (d, J=7.8 Hz, 1H);

441.21 [M+H]+ for LCMS.

EXAMPLE 34 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo pentanamide

2-oxo pentanoic acid (100 mg, 0.86 mmol) is dissolved in THF (17 ml,0.05 M). Next, 9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (351.2 mg, 1.03 mmol) and TEA (0.30 ml, 2.25mmol) are added and the temperature is lowered to −10° C. before POCl₃(0.12 ml, 1.29 mmol) is slowly added in drops. While raising thetemperature slowly to normal temperature, stirring is carried out for 4hours and then THF is concentrated. After adding DCM, washing is carriedout with water and brine. After adding Na₂SO₄ and filtration,concentration is carried out. A column filled with silica is used forpurification to obtain the target compound (150 mg, 39%).

¹H-NMR (300 MHz, CDC13) δ 0.93 (t, J=7.2 Hz, 3H), 1.16-1.20 (m, 6H), 1.6(t, J=7.2 Hz, 3H), 1.60-1.67 (m, 2H), 2.81-2.90 (m, 3H), 6.45 (br, 1H),6.71 (br, 1H), 6.93 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 2H), 7.78 (t,J=7.8 Hz, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.50 (d, J=8.1 Hz, 1H);

439.25 [M+H]+ for LCMS.

EXAMPLE 35 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo octanamide

2-oxo octanoic acid (100 mg, 0.63 mmol) is dissolved in THF (13 ml, 0.05M). Next, 9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (257.3 mg, 0.76 mmol) and TEA (0.22 ml, 1.58mmol) are added and the temperature is lowered to −10° C. before POCl₃(0.09 ml, 1.26 mmol) is slowly added in drops. While raising thetemperature slowly to normal temperature, stirring is carried out for 4hours and then THF is concentrated. After adding DCM, washing is carriedout with water and brine. After adding Na₂SO₄ and filtration,concentration is carried out. A column filled with silica is used forpurification to obtain the target compound (70 mg, 23%).

¹H-NMR (300 MHz, CDC13) δ 0.82-0.88 (m, 3H), 1.16-1.29 (m, 12H),1.49-1.62 (m, 3H), 2.81-2.90 (m, 2H), 6.44 (br, 1H), 6.71 (br, 1H), 6.92(d, J=7.5 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.78 (t J=8.1 Hz, 1H), 8.24(d, J=7.5 Hz, 1H), 8.49 (d, J=8.1 Hz, 1H);

481.20 [M+H]+ for LCMS

EXAMPLE 36 Preparation of Ethyl2-((1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxo acetate

Ethyl 2-((4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b,10-dihydro-9bH-indeno [1, 2-b] benzofuran-9b-yl) amino)-2-oxo acetate(100 mg, 0.23 mmol) is dissolved in EtOH:water=10:1 (5 ml, 0.05 M). Fe(38.5 mg, 0.69 mmol) and 1 drop HCl (Cat) is added. Refluxing is carriedout for 2 hours. After diluting with ethyl acetate (EA) and then washingwith water, its EA layer is extracted. Ethyl acetate is concentrated,and the reactants are dissolved in DCM. After washing with water andbrine, Na₂SO₄ is added, and filtration and concentration is carried out.A column filled with silica is used for purification to obtain thetarget compound (47 mg, 50%).

¹H-NMR (300 MHz, CD30D) δ 1.17 (d, J=6.9 Hz, 6H), 1.29-1.35 (m, 1H),4.27-4.34 (m, 2H), 6.67 (s, 2H), 6.87 (d, J=7.8 Hz, 1H), 6.99 (d, J=6.9Hz, 1H), 7.34-7.47 (m, 2H);

410.7 [M+H]+ for LCMS.

EXAMPLE 37 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3, 3-dimethyl-2-oxobutanamide

9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (500 mg, 1.26 mmol) is added to THF (25 ml, 0.05 M).After adding 3,3-dimethyl-2-oxo butyric acid (137 mg, 1.05 mmol) andthen TEA (0.4 ml, 2.64 mmol), cooling is carried out to −10° C. WhilePOCl₃ (0.149 mg, 1.56 mmol) is slowly added and the temperature ismaintained, stirring is carried out for 3 hours. Concentration iscarried out under reduced pressure, ethyl acetate is added in excess,water is removed with Na₂SO₄, and concentration is carried out underreduced pressure before separation is carried out in a silica gel columnchromatography to obtain the target compound (247 mg, 36%).

¹H-NMR (300 MHz, CDC13): δ 1.15 (d, J=6.6 Hz, 6H), 1.24 (s 9H), 2.82 (m,1H), 5.48 (s, 1H), 6.65 (s, 1H), 6.87 (d, J=7.2 Hz, 1H), 7.34 (d, J=8.4Hz, 1H), 7.59 (m, 1H), 7.81 (m, 2H), 7.92 (s, 1H);

407.92 [M+H]+ for LCMS.

EXAMPLE 38 Preparation of N-(4b hydroxyl-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-4-methyl-2-oxo pentanamide

9b-amino-4b-hydroxy-7-isopropyl-1-nitro-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (300 mg, 0.88 mmol) is added in DCM (6 ml,0.15 M). EDCl (340 mg, 1.76 mmol) and TEA (0.4 ml, 2.64 mmol) are added.After adding HOBT (240 mg, 1.76 mmol) and 4-methyl-2-oxo pentanoic acid(120 mg, 0.88 mmol), stirring is carried out at normal temperature for12 hours. DCM is farther added for dilution and then washing is carriedout with water. Water is removed with Na₂SO₄, concentration is carriedout under reduced pressure, and then purification is carried out withsilica gel column chromatography to obtain the target compound (68 mg,16%).

¹H-NMR (300 MHz, CDC13): δ 0.92 (t, J=5.3. Hz, 6H), 1.17 (t, J=3.9 Hz,6H), 2.16 (m, 2H), 2.70 (m, 2H), 2.74 (m, 2H), 6.70 (s, 1H), 6.92 (d,J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 2H), 7.77 (t, J=7.8 Hz, 1H), 8.23 (d,5=7.6 Hz, 1H), 8.48 (d, J=7.9 Hz, 1H);

452.90 [M+H]+ for LCMS.

EXAMPLE 39 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenyl butanamide

While 2-oxo-4-phenyl butyric acid (50 mg, 0.28 mmol) is added in DCM(0.1 M, 3.0 ml) at 0° C. and stirred, HATU (160 mg, 0.42 mmol) and thenDIPEA (0.07 ml, 0.42 mmol) are added prior to stirring. Finally,9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (83 mg, 0.28 mmol) is added and stirring is carriedout at normal temperature for 12 hours. Upon completion of the reaction,water and DCM are used for extraction and washing with water is carriedout again before water is removed with Na2SO4 and then concentrationunder reduced pressure is carried out. Finally, a column filled withsilica is used for purification to obtain the target compound (35 mg,28%).

¹H-NMR (300 MHz, CD30D): δ 1.15-1.18 (m, 6H), 1.91-.2.15 (m, 2H),2.72-2.88 (m, 3H), 3.07-3.11 (m, 1H), 6.67 (s, 1H), 6.88-6.90 (m, 1H),7.14-7.22 (m, 4H), 7.34-7.39 (m, 1H), 7.52-8.03 (m, 5H);

456.51 [M+H]+ for LCMS.

EXAMPLE 40 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-2-oxo pentanamide

After N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b, 10-dihydro-9bH-indeno[1, 2-b] benzofuran-9b-yl)-3-methyl-2-oxo pentanamide (80 mg, 0.18 mmol)is dissolved in EtOH:H2O (10:1) (0.02 M, 9.0 ml), iron powder (30 mg,0.54 mmol) is added and stirred before conc. HCl (2 drops) is finallyadded slowly and then the reaction is carried out at 120° C. for 3hours.

Upon completion of the reaction, cooling is carried out to normaltemperature, concentration under reduced pressure is carried out, waterand ethyl acetate are used for extraction, and washing with water iscarried out again before water is removed with Na₂SO₄ and thenconcentration is carried out under reduced pressure. Finally, a columnfilled with silica is used for purification to obtain the targetcompound (40 mg, 53%).

¹H-NMR (300 MHz, CD30D): δ 0.85-0.94 (m, 3H), 1.04-1.09 (m 3H), 1.18 (d,J=6.7 Hz, 6H), 1.30-1.40 (m, 2H), 2.77-2.89 (m, 1H) 6.65-6.71 (m, 2H),6.86-6.88 (m, 1H), 6.98-7.01 (m, 1H), 7.32-7.38 (m, 1H), 7.42-7.48 (m,1H);

422.89 [M+H]+ for LCMS.

EXAMPLE 41 Preparation of 3-bromo-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo propanamide

9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (425 mg, 1.44 mmol) is added in THF (10 ml,0.1 M). After slowly adding TEA (0.417 ml, 1.29 mmol),3-bromo-2-oxopropionic acid (200 mg, 1.198 mmol) is added. After coolingto −10° C. and then slowly adding a 0.2 M phosphorous oxy chloridesolution (12.0 ml, 2.40 mmol), stirring is carried out for 5-6 hours.Upon completion of the reaction, concentration under reduced pressure iscarried out to remove THF and water and ethyl acetate are used forextraction. After washing with water is carried out again, water isremoved with Na₂SO₄ and concentration under reduced pressure is carriedout. Finally, a column filled with silica is used for purification toobtain the target compound (70 mg, 13%).

¹H-NMR (300 MHz, CDC13) δ 1.19 (dd, J=6.9 Hz, J=2.4 Hz, 6H), 2.87 (sept,J=6.9 Hz, 1H), 4.28-4.51 (m, 2H), 6.79 (s, 1H) 6.97 (d, J=8.1 Hz, 1H),7.64-7.71 (m, 2H), 7.88-7.93 (m, 2H), 8.07 (d, J=7.8 Hz, 1H).

EXAMPLE 42 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2,4-dioxo-4-(pyridyn-4-yl)butanamide

2,4-dioxo-4-(pyridine-4-yl) butyric acid (25 mg, 0.13 mmol) is added toDCM (1.5 ml) and cooled to 0° C. HATU (74 mg, 0.19 mmol) and DIPEA(0.034 ml, 0.19 mmol) are added. After 5 minutes,9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (42 mg, 0.14 mmol) is added and then stirring iscarried out for 24 hours. Upon quenching with water, DCM (50 ml×2) isadded. After water and ethyl acetate is used for extraction and thenwashing with water is carried out again, water is removed with Na₂SO₄and concentration under reduced pressure is carried out. Finally, acolumn filled with silica is used (10% MeOH in DCM) for purification toobtain the target compound (45 mg, 74%).

¹H-NMR (300 MHz, CD30D) δ 1.19 (d, J=6.9 Hz, 6H), 2.83 (sept, J=6.9 Hz,1H), 6.70 (s, 1H), 6.91 (s, 1H), 7.38 (s, 1H) 7.64 (s, 1H), 7.83-7.85(m, 4H), 7.97 (s, 1H), 8.67-8.76 (m, 2H);

470.77 [M+H]+ for LCMS.

EXAMPLE 43 Preparation of 4-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl amino)-4-oxo butanoic acid

4-((4b-hydroxy-7-isopropyl-10-oxo-4b, 10-dihydro-9bH-indeno [1,2-b]benzofuran-9b-yl) amino)-4-oxo butyric acid triethyl amine salt (300 mg,0.60 mmol) is added in EtOAc (10 ml, 0.06 M). After adding HCl (1 N, 10ml) at normal temperature, stirring is carried out for 5 min. Afterwater and ethyl acetate are used for extraction and then washing withwater is carried out again, water is removed with Na₂SO₄ andconcentration under reduced pressure is carried out. Finally, a columnfilled with silica is used for purification to obtain the targetcompound (240 mg, Quant.).

¹H-NMR (300 MHz, CD30D) δ 1.16 (d, J=6.9 Hz, 6H), 2.53-2.60 (m, 4H),2.83 (sept, J=6.9 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz,1H), 7.57-7.60 (m, 1H), 7.74-7.83 (m, 2H), 7.90 (s, 1H);

395.92 [M+H]+ for LCMS.

EXAMPLE 44 Preparation of N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N4, N4-dimethylsuccinamide

4-((4b-hydroxy-7-isopropyl-10-oxo-4b, 10-dihydro-9bH-indeno [1,2-b]benzofuran-9b-yl) amino)-4-oxo butyric acid (100 mg, 0.25 mmol) is addedin DCM (2.5 ml) and cooled to 0° C. After HATU (144 mg, 0.38 mmol) andDIPEA (0.110 ml, 0.63 mmol) are added, stirring is carried out for 5min. After dimethyl amine chloride (25 mg, 0.30 mmol), stirring iscarried out for 24 hours. Upon quenching with water, DCM (50 ml×2) isadded. After water and ethyl acetate are used for extraction and thenwashing with water is carried out again, water is removed with Na₂SO₄and concentration under reduced pressure is carried out. Finally, acolumn filled with silica is used (2:1=EtOAc:Hx) for purification toobtain the target compound (60 mg, 56%).

¹H-NMR (300 MHz, CD30D) δ 1.16 (d, J=6.9 Hz, 6H), 2.59 (m, 4H), 2.81(sept, J=6.9 Hz, 1H), 2.90 (s, 3H), 3.01 (s, 3H), 6.86 (d, J=7.8 Hz,1H), 7.36 (d, J=7.8 Hz, 1H), 7.56-7.59 (m, 1H), 7.73-7.82 (m, 2H),7.90-7.92 (m, 1H);

422.96 [M+H]+, 844.92 [2M+H]+ for LCMS.

EXAMPLE 45 Preparation of N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N4-isopropyl succinamide

4-((4b-hydroxy-7-isopropyl-10-oxo-4b, 10-dihydro-9bH-indeno [1,2-b]benzofuran-9b-yl) amino)-4-oxo butyric acid (100 mg, 0.25 mmol) is addedin DCM (2.5 ml) and cooled to 0° C. After adding HATU (144 mg, 0.38mmol) and DIPEA (0.066 ml, 0.38 mmol), stirring is carried out for 5min. After adding isopropyl amine (0.025 ml, 0.30 mmol), stirring iscarried out for 24 hours. Upon quenching with water, DCM (50 ml×2) isadded. After water and ethyl acetate are used for extraction and thenwashing with water is carried out again, water is removed with Na₂SO₄and concentration under reduced pressure is carried out. Finally, acolumn filled with silica is used (DCM:EtOAc=1:1) for purification toobtain the target compound (30 mg, 27%).

¹H-NMR (300 MHz, CD30D) δ 1.10 (d, J=6.6 Hz, 6H), 1.16 (d, J=6.9 Hz,6H), 2.38 (t, J=7.8 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 2.82 (sept, J=6.9Hz, 1H), 3.92 (sept, J=6.6 Hz, 1H) 6.64 (s, 1H), 6.86 (d, J=7.8 Hz, 1H),7.35 (d, J=7.8 Hz, 1H), 7.53-7.83 (m, 4H);

436.91 [M+H]+, 873.01 [2M+H]+ for LCMS.

EXAMPLE 46 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)cyanamide

9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (295 mg, 1.0 mmol) is added in THF (5 ml, 0.1 M) andcooled to 0° C. TEA (0.14 ml, 1.0 mmol) is slowly added. A cyanogenbromide (95.2 mg, 0.9 mmol) solution 5 ml is slowly added for 15 min andstirred. Stirring is carried out at 0° C. for 3 hours. Solid is filteredand separated and the solid is washed with THF. The liquid separated byfiltration is concentrated under reduced pressure (DCM/Hx) andrecrystallized to obtain the target compound (150 mg, 47%).

¹H-NMR (300 MHz, CD30D) δ 1.14-1.20 (s. 6H), 2.86 (sept, J=6.9 Hz, 1H),6.80 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.67-7.72(m, 1H), 7.84-8.10 (m, 3H);

320.77 [M+H]+, 640.86 [2M+H]+ for LCMS.

EXAMPLE 47 Preparation of N1-(4-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-(2,6-dimethylphenyl)oxal amide

After adding N1-(2, 6-dimmethylphenyl)-N2-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno [1,2-b] benzofuran-9b-yl) oxal amide (70 mg, 0.136mmol), Fe (23 mg, 0.407 mmol) and HCl (2 drops) are added in the 10:1 10mL mixture of EtOH and H₂O, stirring is carried out at 90° C. for 2hours. After filtration with celite, concentration is carried out. Afterdiluting with ethyl acetate (EA) and washing with water, the EA layer isextracted. The reactants are concentrated and purification is carriedout in a silica gel column chromatography (50% EA in Hex) to obtain thetarget compound (43 mg, 65%).

¹H-NMR (500 MHz, DMSO-d6): δ 1.14 (s, 6H), 2.12 (s−6H), 2.75-2.91 (m,1H), 6.66-6.70 (m, 3H), 6.85-6.92 (m, 2H), 7.05-7.10 (m, 3H), 8.09 (s,1H), 8.39 (s, 1H), 10.12 (s, 1H);

485.74 [M+H]+971.09 [2M+H]+ for LCMS.

EXAMPLE 48 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(4-methylpiperazin-1-yl)-2-oxo acetamide

After 2-(4-methyl piperazin-1-yl)-2-oxo acetic acid (80 mg, 0.46 mmol)is added in DCM (0.1 M, 5.0 ml) at 0° C. and stirred, HATU (262 mg, 0.69mmol) and DIPEA (0.12 ml, 0.69 mmol) are added and then stirred.Finally, 9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno[1,2-b] benzofuran-10-one (150 mg, 0.51 mmol) is added and stirring iscarried out at normal temperature for 12 hours. Upon completion of thereaction, the solid formed is filtered and then dissolved in EA again.Water and ethyl acetate are used for extraction and washing is carriedout with water before water is removed with Na₂SO₄ and concentrationunder reduced is carried out to obtain the target compound (70 mg, 33%).

¹H-NMR (300 MHz, CD30D): δ 1.15 (d, J=6.9 Hz, 6H), 2.54 (s, 3H),2.79-2.81 (m, 4H), 3.70 (s, 2H), 3.82 (s, 2H), 6.66 (s, 1H), 6.87 (d,J=7.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.71 (s, 2H), 7.84 (s, 2H):

449.86 [M+H]+ for LCMS.

EXAMPLE 49 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-4-methyl-2-oxo pentanamide

N-(4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b, 10-dihydro-9bH-indeno[1,2-b] benzofuran-9b-yl)-4-meth)-2-oxo pentanamide (50 mg, 0.11 mmol)is added in EtOH:H₂O (10:1, 5.5 ml, 0.02 M) and Fe (19 mg, 0.33 mmol)and acetic acid (2 drops) are added before heating and stirring iscarried out at 90° C. for 3 hours. A separation tube filled with celiteis used to remove Fe and then concentration under reduced pressured iscarried out. After ethyl acetate is added in excess, washing with wateris carried out, water is removed with Na₂SO₄, and concentration underreduced pressure is carried out, separation is carried out in a silicagel column chromatography to obtain target compound (36 mg, 78%).

¹H-NMR (300 MHz, CDC13): δ 0.93 (d, J=4.5 Hz, 6H), 1.16 (d, J=6.8 Hz,6H), 2.13 (m, 1H), 2.65 (d, J=6.7 Hz, 2H), 2.84 (t, J=3.5 Hz, 1H), 6.67(d, J=11.0 Hz, 2H), 6.86 (d, J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 7.34(d, J=8.0 Hz, 1H), 7.44 (t, 8.1 Hz, 1H);

423.48 [M+H]+ for LCMS.

EXAMPLE 50 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo hexanamide

N-(4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b, 10-dihydro-9bH-indeno[1,2-b] benzofuran-9b-yl)-2-oxo hexanamide (50 mg, 0.11 mmol) is addedin EtOH:H₂O (10:1, 5.5 ml, 0.02 M) and Fe (19 mg, 0.33 mmol) and aceticacid (2 drops) are added before heating and stirring is carried out at90° C. for 3 hours. A separation tube filled with celite is used toremove Fe and then concentration under reduced pressured is carried out.After ethyl acetate is added in excess, washing with water was carried,water is removed with Na₂SO₄, and concentration under reduced pressureis carried out, separation is carried out in a silica gel columnchromatography to obtain target compound (21 mg. 42%).

¹H-NMR (300 MHz, CD30D): δ 0.89 (s, 4H), 1.16 (d, J=6.8 Hz 6H), 1.53 (m,2H), 2.79 (m, 3H), 2.98 (s, 1H), 3.63 (s, 1H), 6.65 (m, 2H, 6.86 (d,J-6.3 Hz, 1H), 6.98 (d, J=6.2 Hz, 1H), 7.33 (m, 1H), 7.44 (m, 1H);

450.01 [M+H]+ for LCMS.

EXAMPLE 51 Preparation of N-(4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2 mesityl-2-oxo acetamide

After dissolving mesityl glyoxalic acid (100 mg, 0.52 mmol) is dissolvedin DCM (5.2 ml, 0.1 M), HATU (296.6 mg, 0.78 mmol) and DIPEA (0.136 ml,0.78 mmol) are added. Finally, an amine compound (193.9 mg, 0.57 mmol)is added before stirring is carried out for 12 hours. Upon completion ofthe reaction, washing is carried out with dichloromethane, NaHCO₃aqueous solution and water and then water is removed with Na₂SO₄ beforeconcentration under reduced pressure is carried out. Separation iscarried out in a silica gel column chromatography to obtain the targetcompound (91 mg, 34%).

¹H-NMR (300 MHz, CD30D) δ 1.17 (d, J=6.6 Hz, 6H), 2.22 (d, J=9.6 Hz,9H), 6.74 (s, 1H), 6.82 (s, 1H), 6.95 (d, J=7.8 Hz, 2H) 7.44 (d, J=7.8Hz, 1H), 7.79 (s, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.46 (s, 1H);

515.0 [M+H]+ for LCMS.

EXAMPLE 52 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo pentanamide

N-(4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b, 10-dihydro-9bH-indeno[1,2-b] benzofuran-9b-yl)-2-oxo pentanamide (50 mg, 0.114 mmol) isdissolved in EtOH:water=10:1 (5 ml, 0.02 M) before Fe (19.1 mg, 0.34mmol) and one drop of HCl (Cat) is added and then stirring is carriedout at 90° C. for 4 hours. Upon completion of the reaction, washing iscarried out with dichloromethane and water and water is removed withNa₂SO₄to obtain the target compound (19.7 mg, 42%) with prep TLC.

¹H-NMR (300 MHz, CD30D) δ 0.93 (t, 7.5 Hz, 3H), 1.17 (d6.6 Hz, 6H), 1.28(br, 1H), 1.57-1.64 (m, 2H), 2.74-2.85 (m, 2H), 6.66-6.70 (m, 2H), 6.86(d, J=7.5 Hz, 1H), 6.99 (d, J=7.5 Hz, 1H) 7.35 (d, J=7.5 Hz, 1H),7.43-4.47 (m, 1H);

409.8 [M+H]+ for LCMS.

EXAMPLE 53 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenyl butanamide

After dissolving 2-oxo-4-phenyl butyric acid (50 mg, 0.28 mmol) in DCM(2.81 ml, 0.1 M), HATU (160 mg, 0.42 mmol) and DIPEA (0.073 ml, 0.42mmol) are added, and a nitro compound (105.1 mg, 0.31 mmol) is added,and then stirring is carried out at room temperature for 12 hours. Uponcompletion of the reaction, dichloromethane, an NaHCO₃ aqueous solution,and water are used for washing before water is removed with Na₂SO₄ andseparation is carried out in a silica gel column chromatography toobtain the target compound (35 mg, 25%).

¹H-NMR (300 MHz, CD30D) δ 1.18 (d, J=6.3 Hz, 6H), 2.82-2.93 (m, 4H),3.10-3.11 (m, 1H), 6.73 (s, 1H), 6.94 (d, 1=7.2 Hz, 1H), 7.14-7.26 (m,5H), 7.39 (t, 7.2 Hz, 1H), 7.86-7.89 (m, 1H), 8.51-8.55 (m, 1H);

501.51 [M+H]+ for LCMS.

EXAMPLE 54 Preparation of N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-mesityl-2-oxo acetamide

N-(4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b, 10-dihydro-9bH-indeno[1,2-b] benzofuran-9b-yl)-2-oxo pentanamide (50 mg, 0.114 mmol) isdissolved in EtOH:water=10:1 (5 ml, 0.02 M) before Fe (19.1 mg, 0.34mmol) and one drop of HCl (Cat) are added and then stirring is carriedout at 90° C. for 4 hours. Upon completion of the reaction, washing iscarried out with dichloromethane and water and prep TLC is used toobtain the target compound (19.7 mg, 42%).

¹H-NMR (300 MHz, CD30D) δ 1.88 (d, J=6.6 Hz, 6H), 2.23 (d, J=9.6 Hz,9H), 2.79-2.86 (m, 1H), 6.65 (d, 7.5 Hz, 2H), 6.83 (s, 2H), 6.89 (d,J=7.5 Hz, 1H), 6.98 (d, J=7.5 Hz, 1H), 7.41 (t, J=8.1 Hz, 2H);

485.8 [M+H]+ for LCMS.

EXAMPLE 55 Preparation of N, N′-di-tert-butoxy carbonyl[1]-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]guanidine

In 9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (295 mg, 1.00 mmol) is added DMF (5 ml, 0.2 M) and1,3-bis (tert-butoxy carbonyl)-2-methyl-2-thiopseudo urea (305 mg, 1.05mmol). After adding HgCl₂ (298 mg, 1.10 mmol) and then adding triethylamine (0.31 ml, 2.20 mmol) at 0° C., stirring is carried out for 90 min.

Upon completion of the reaction, ethyl acetate (50 ml) is added and thenfiltration is carried out on celite. After washing the filtrate withwater and brine, water is removed with Na₂SO₄ and then separation iscarried out in a silica gel column chromatography (10% ethyl acetate inhexanes) to obtain the target compound (94 mg, 18%).

¹H-NMR (300 MHz, CD30D) δ 1.18 (d, J=6.9 Hz, 6H), 1.20 (s, 9H), 1.51 (s,9H), 2.82 (sept, J=6.9 Hz, 1H), 6.66 (s, 1H), 6.87 (br, 1H), 7.34 (br,1H), 7.72-7.84 (m, 4H);

537.89 [M+H]+ for LCMS.

EXAMPLE 56 Preparation of Tert-butyl (4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)ethan-1,2-diyl dicarbamate

In 7-isopropyl-10H-4b, 9b-(epoxy metanooxy) indeno [1,2-b]benzofuran-10, 12-dione (170 mg, 0.5 mmol) is added THF:DMF (8:1) andtert-butyl (2-amino ethyl) carbamate (80 mg, 0.50 mmol). Afterward DMAP(2-3 mg) and TEA (0.14 ml, 1.11 mmol) are added before stirring iscarried out at room temperature for 6 hours. Upon completion of thereaction, concentration under reduced pressure is carried out and thenseparation is carried out in a silica gel column chromatography (20%EtAc in hexane) to obtain the target compound (200 mg, 83%).

¹H-NMR (300 MHz, CDC13) δ 1.15 (dd, J=6.9 Hz, J=2.4 Hz, 6H), 1.41 (s,9H), 2.80 (septet, J=6.9 Hz, 1H), 3.12-3.22 (m, 4H), 5.03 (s, 1H), 6.65(s, 1H), 6.77 (d, J=7.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.48-7.53 (m,1H), 7.70-7.79 (m, 2H), 7.87 (d, J=7.5 Hz, 1H);

483.23 [M+H]+, 966.40 [2M+H]+ for LCMS.

EXAMPLE 57 Preparation of 4-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-4-oxo butanoic acid

In 9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (295 mg, 1.0 mmol) and anhydrous succinic acid areadded dry THF (10 ml, 0.1 M) and TEA (0.167 ml, 1.20 mmol). After addingDMAP (10 mg), stirring is carried out in a refluxing apparatus for 8hours. Upon completion of the reaction, cooling to room temperature iscarried out and then solid is filtered. The filtrate is washed with THFto obtain the target compound (360 mg, 73%).

¹H-NMR (300 MHz, DMSO-d6) δ 0.97 (t, J=7.2 Hz, 9H), 1.11 (d, J=6.9 Hz,6H), 2.28-2.30 (m, 2H), 2.38-2.40 (m, 2H), 2.51-2.55 (m, 6H), 2.79(sept, J=6.9 Hz, 1H), 6.64 (s, 1H), 6.85 (d, J=7.8 Hz, 1H), 7.73-7.77(ra, 4H), 8.72 (br, 1H);

395.85 [M+H]+ for LCMS.

EXAMPLE 58 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) 2-oxo-2-(3,4,5-trimethoxyphenyl)acetamide

After 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b, 9b-dihydro-10H-indeno[1, 2-b] benzofuran-10-one (72 mg, 0.21 mmol) is added in DMF (3 ml, 0.1 mmol), HATU (118 mg, 0.31 mmol) and DIPEA (0.6 ml, 0.31 mmol) areadded. After adding 2-oxo-2-(3, 4, 5-trimethoxy phenyl) acetic acid (50mg, 0.21 mg), stirring is carried out at normal temperature for 5 hours.After adding DCM in excess and washing with water, water is removed withNa₂SO₄ and then concentration under reduced pressure is carried out.Separation is carried out in a silica gel column chromatography toobtain the target compound (55 mg, 46%).

¹H-NMR (300 MHz, CDC13): δ 1.19 (d, J=10.0 Hz, 6H), 2.16 (s, 9H), 2.84(m, 1H), 6.49 (s, 1H), 6.72 (s, 1H), 6.94 (d, J=7.9 Hz, 1H), 7.46 (d,J=7.9 Hz, 1H), 7.60 (s, 1H), 7.65 (s, 2H), 7.79 (t, J=7.8 Hz, 1H), 8.27(d, J=7.6 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H);

562.79 [M+H]+ for LCMS.

EXAMPLE 59 Preparation of N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenyl butanamide

After dissolving N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno [1,2-b] benzofuran-9b-yl)-2-oxo-4-phenylbutanamide (50 mg, 0.10 mmol) in ECOH:water=10:1 (2 ml, 0.05 M), Fe(16.7 mg, 0.30 mmol) is added and then stirred. Lastly, one drop of HClis added and then stirring is carried out at 90° C. for 12 hours. Uponcompletion of the reaction, cooling to normal temperature is carried outand then concentration under reduced pressure is carried out. Water andethyl acetate are used for extraction before washing with water,removing water with Na₂SO₄, and concentration under reduced pressure.Finally, a column filled with silica is used for purification to obtainthe target compound (20 mg 43%).

¹H-NMR (300 MHz, CD30D) δ 1.17 (d, J=6.3 Hz, 6H), 2.74-2.97 (m, 4H),3.06-3.13 (m, 1H), 6.66-6.69 (m, 2H), 6.87 (d, J=7.2 Hz, 1H), 6.99 (t,J=7.2 Hz, 1H), 7.14-7.23 (m, 5H), 7.35 (d, J=7.8 Hz, 1H), 7.44 (t, J=7.8Hz, 1H);

471.9 [M+H]+ for LCMS.

EXAMPLE 60 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetimide amide

After dissolving 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (150 mg, 0.5 mmol) inacetonitrile (ACN) (5 ml, 0.1 M), stirring is carried out while addingethyl acetamidate (189 mg, 1.5 mmol).

After adding DIPEA (0.02 ml, 1.27 mmol), refluxing is carried out for 12hours. Upon completion of the reaction, cooling to normal temperature iscarried out and then concentration under reduced pressure is carriedout. Water and ethyl acetate are used for extraction before washing withwater, removing water with Na₂SO₄, and concentration under reducedpressure. Finally, DCM/Hx is added to the mixture for recrystallizationto obtain the target compound (38 mg, 23%).

¹H-NMR (300 MHz, CD30D) δ 1.19 (d, J=6.9 Hz, 6H), 1.96 (s, 3H), 2.81(sept, J=6.9 Hz, 1H), 6.60 (s, 1H), 6.79 (d, J=8.1 Hz, 1H), 7.30 (d,J=8.1 Hz, 1H), 7.52-7.54 (m, 1H), 7.73-7.80 (m, 3H);

336.88 [M+H]+ for LCMS.

EXAMPLE 61 Preparation of 1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)thiourea

After dissolving 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (2.95 g, 10.0 mmol) inacetone:water (2:1, 100 ml), potassium thiocyanate (4.86 g, 49.99 mmol)are added. After adding conc. HCl (5 ml), stirring is carried out atnormal temperature for 12 hours. Upon completion of the reaction, waterand ethyl acetate are used for extraction and then washing with brine iscarried out again. After removing water with Na₂SO₄ and thenconcentrating under reduced pressure, the mixture obtained is purifiedin a silica gel column chromatography (33% EA in Hex) to obtain thetarget compound (2.64 g, 75%).

¹H-NMR (300 MHz, CD30D) δ 1.50-1.22 (m, 6H), 2.83 (sept, J=6.9 Hz, 1H),6.61 (s, 1H), 6.86 (d, J=8.1 Hz, 1H), 7.35-7.89 (m, 5H);

354.87 [M+H]+, 708.97 [2M+H]+ for LCMS.

EXAMPLE 62 Preparation of 7-isopropyl-4b-methoxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl ethyl carbamate

9b-hydroxy-7-isopropyl-4b-methoxy-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (950 mg, 3.07 mmol) is added in DCM (12 ml) at 0° C.and stirred before triphosgene (909 mg, 3.07 mmol) is dissolved in TEA(0.43 ml, 3.07 mmol) and then slowly added. After approximately 10 min,concentration under reduced pressure is carried out to remove any excessphosgene and then DCM (12 ml) is again dissolved before a solution (0.77ml, 1.53 mmol) prepared by mixing ethyl amine with methanol (2.0 M) isadded and then TEA (0.43 ml, 3.07 mmol) is added. After reacting atnormal temperature for 2 hours, water and DCM are used for extractionand washing with brine is carried out again. After removing water withNa₂SO₄ and then concentrating under reduced pressure, the mixtureobtained is purified in a silica gel column chromatography (10% EA inHex) to obtain the target compound (350 mg, 60%).

¹H-NMR (300 MHz, CDC13) δ 1.09 (t, J=7.2 Hz, 3H), 1.20 (dd, J=6.9 Hz,J=4.8 Hz, 6H) 2.87 (septet, J=6.9 Hz, 1H), 3.44-3.55 (m, 2H), 3.65 (s,1H), 3.71 (s, 3H), 6.77 (s, 1H), 6.88-6.91 (d, J=9 Hz, 1H), 7.46-7.55(m, 3H), 7.61 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H);

382.29 [M+H]+ for LCMS.

EXAMPLE 63 Preparation of tert-butyl(2-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxoethyl)carbamate

While glycine (650 mg, 3.72 mmol) is dissolved in DCM (20 ml, 0.2 M) at0° C. and then stirred, HATU (1.54 g, 4.06 mmol) and DIPEA (0.734 ml,4.06 mmol) are added to carry out the reaction. After approximately 5min, 9b-amino-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (0.025 ml, 0.30 mmol) is added to carry out thereaction for 6 hours. Upon completion of the reaction, water and DCM (50ml×2) are used for extraction and washing is carried out again withbrine. After removing water with Na₂SO₄ and then concentrating underreduced pressure, the mixture obtained is purified in a silica gelcolumn chromatography (10% EA in Hex) to obtain the target compound(1.30 g, 85%).

¹H-NMR (300 MHz, CD30D) δ 1.15 (d, J=6.9 Hz, 6H), 1.41 (s, 9H), 2.81(sept, J=6.9 Hz, 1H), 3.82 (s, 2H), 6.65 (s, 1H), 6.86 (d, J=7.8 Hz,1H), 7.34 (d, J=7.8 Hz, 1H), 7.57 (br, 1H) 7.77-7.90 (br, 3H);

452.83 [M+H]+, 904.94 [2M+H]+ for LCMS.

EXAMPLE 64 Preparation of 2-amino-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide

While tert-butyl (2-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno [1,2-b] benzofuran-9b-yl) amino)-2-oxo ethyl)carbamate (900 mg, 2.00 mmol) is added in DCM (10 ml, 0.2 M) andstirred, trifluoroacetic acid (1.52 ml, 20.0 mmol) is added. Afterreacting at normal temperature for 12 hours, DCM (150 ml) andover-saturated NaHCO₃ (50 ml×2) is used for extraction upon completionof the reaction and then brine (50 ml) washing is carried out again.Water was removed with Na₂SO4 and concentration under reduced pressureis carried out to obtain the target compound (670 mg, 96%).

¹H-NMR (300 MHz, CD30D) δ 1.16 (d, J=6.9 Hz, 6H), 2.82 (sept, J=6.9 Hz,1H), 3.34 (s, 2H), 6.65 (s, 1H), 6.86 (d, J=7.8 Hz, 1H), 7.35 (d, J=7.8Hz, 1H), 7.69-7.72 (m, 2H);

352.51 [M+H]+, 704.85 [2M+H]+ for LCMS.

EXAMPLE 65 Preparation of 4b-hydroxy-7, 8-dimethyl-9b-(methyl amino)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one

After dissolving 9b-chloro-4b-hydroxy-7, 8-dimethyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (2 g, 6.65 mmol) in THF(66 ml, 0.1 M), the reaction temperature is kept at −200° C. Afteradding methyl amine (6.65 ml, 13.30 mmol) in that order, the reaction iscarried out for 5 hours.

Upon completion of the reaction, THF is concentrated under reducedpressure and removed and then DCM and water are used for extractionbefore brine washing is carried out again. After removing water withNa₂SO₄, silica gel chromatography is used for purification to obtain thetarget compound (710 mg, 36%).

¹H-NMR (300 MHz, CDC13) δ 2.17 (s, 6H), 2.31 (s, 6H), 6.64 (s, 1H), 7.13(s, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.76 (t, J=7.5 Hz, 2H), 7.98 (d, J=7.5Hz, 1H);

295.44 [M+H]+ for LCMS.

EXAMPLE 66 Preparation of N-tert butoxy carbonyl[N3-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]guanidine

After dissolving N′, N′-di-tert-butoxycarbonyl[11-(4b-hydroxy-7-isopropyl-10-oxo-4b, 10-dihydro-9bH-indeno [1,2-b]benzofuran-9b-yl)] guanidine (200 mg, 0.37 mmol) in MeOH (2 ml, 0.2 M),stirring is carried out while adding 2 N HCl (1.0 ml, 5 eq. approx.).After reacting at normal temperature for 12 hours, concentration underreduced pressure is carried out upon completion of the reaction before asilica gel column chromatography (3% MeOH in DCM) is used forpurification immediately. Concentration under reduced pressure anddrying is carried out to obtain the target compound (115 mg, 71%).

¹H-NMR (300 MHz, CD30D) δ 1.19 (d, J=6.9 Hz, 6H), 1.50 (s, 9H), 2.85(sept, J=6.9 Hz, 1H), 6.68 (s, 1H), 6.88 (d, J=7.8 Hz, 1H), 7.38 (d,J=7.8 Hz, 1H), 7.54-7.62 (m, 2H), 7.73-7.78 (m, 2H);

437.86 [M+H]+, 875.03 [2M+H]+ for LCMS.

EXAMPLE 67 Preparation of N,N′-di-tert butoxy carbonyl[1-(4b-hydroxy-7,8-dimethyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]-1-methyl guanidine

After dissolving 4b-hydroxy-7, 8-dimethyl-9b-(methyl amino)-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (295.3 mg, 1.0 mmol) inDMF (0.2 M, 5 ml), 1, 1, 2, 3, 3-pentamethyl isothiouronium iodide(287.7 mg, 1.05 mmol) is added. While stirring at 0° C., TEA and HgCl₂(298.7 mg, 1.1 mmol) are added to carry out the reaction for 2 hours.Upon completion of the reaction, water and ethyl acetate are used forextraction and brine washing is carried out again. After removing waterwith Na₂SO₄, a silica gel chromatography is used for purification toobtain the target compound (120 mg, 22%).

¹H-NMR (300 MHz, CD30D) δ 1.46 (s, 9H), 1.49 (s, 9H), 2.21 (s, 6H), 2.26(s, 3H), 6.62 (s, IH), 7.20 (s, 1H), 7.74-7.50 (m, 2H), 7.62 (d, J=6.9Hz, 1H), 7.81 (d, J=6.9 Hz, 1H);

538.3 [M+H]+ for LCMS.

EXAMPLE 68 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) thiopene-2-sulfonamide

After adding and dissolving 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (500 mg, 1.69 mmol) inacetonitrile (ACN) (17 ml, 0.1 M), benzene sulfonyl chloride (0.24 ml,1.86 mmol) is added. After adding pyridine (0.27, 3.38 mmol), thereaction is carried out at normal temperature for 12 hours. Uponcompletion of the reaction, water and DCM are used for extraction andthen brine washing is carried out. After removing water with Na₂SO₄,purification is carried out on silica gel column chromatography toobtain the target compound (460 mg, 62%).

¹H-NMR (300 MHz, CDC13) δ 1.15 (d, J=6.9 Hz, 6H), 2.71-2.80 (m, 1H),6.00 (br, 1H), 6.09 (br, 1H), 6.30 (d, J=7.8 Hz, 1H), 6.52 (d, J=7.8 Hz,1H), 6.70 (s, 1H), 6.77 (t, J=4.5 Hz, 1H), 6.93-6.94 (m, 1H), 7.45 (d,J=4.5 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.75-7.84 (m, 2H), 8.03 (d, J=7.8Hz, 1H);

440.0 [M+H]+ for LCMS.

EXAMPLE 69 Preparation of N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)benzene sulfonamide

After dissolving 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (500 mg, 1.7 mmol) inDCM (17 ml, 0.1 M) and adding benzene sulfonyl chloride (0.24 ml, 1.86mmol), K₂CO₃ (467 mg, 3.38 mmol) and 18-crown-6 (89 mg, 0.34 mmol) areadded and then stirring is carried out at room temperature for 12 hours.After diluting the reaction mixture with DCM and washing with water andbrine, Na₂SO₄ is used to remove water and then concentration underreduced pressure is carried out. Purification is carried out in a silicagel column chromatography to obtain the target compound (190 mg, 26%).

¹H-NMR (300 MHz, CDC13) δ 1.22 (d, J=7.8 Hz, 6H) 2 89-2.93 (m, 1H), 6.81(s, 1H), 7.05 (d, J=8.1 Hz 1H), 7 49 (t, J=7.5 Hz, 2H), 7.59-7.69 (m,2H), 7.83-7.95 (m 3H), 8 11 (d, J=7.8 Hz, 3H);

434.0 [M+H]+ for LCMS.

EXAMPLE 70 Preparation of 4b-hydroxy-7, 8-dimethyl-9b-(pyridin-2-ylamino)-4b, 9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one

After dissolving 9b-chloro-4b-hydroxy-7, 8-dimethyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (300 mg, 1.0 mmol) inTHF (10 ml, 0.1 M) and cooling to −30° C., 2-amino pyridine (98.5 mg,1.05 mmol) is added. After adding TEA (0.153 ml, 1.10 mmol) at the sametemperature, the reaction mixture is allowed to stand for 2 hours untilit reaches room temperature. Upon completion of the reaction,concentration under reduced pressure is carried out.

After the concentrated reaction mixture is diluted with ethyl acetate(100 ml), and then washed with water and brine; water is removed withNa₂SO₄ and then concentration under reduced pressure is carried out.Purification is carried out in a silica gel column chromatography(20-25%. EtAc in hexane) to obtain the target compound (150 mg, 42%).

¹H-NMR (300 MHz, CDC13) δ 2.07 (s, 3H), 2.11 (s, 3H), 5.50 (s, 1H), 6.57(s, 1H), 6.64-6.68 (m, 1H), 6.74 (d, J=8.4 Hz, 1H), 7.01 (s, 1H),7.43-7.55 (m, 2H), 7.78-7.84 (m, 2H), 7.92 (d, J=4.8 Hz, 1H), 8.06 (d,J=7.8 Hz, 1H), 9.06 (s, 1H);

359.1 [M+H]+ for LCMS.

EXAMPLE 71 Preparation of N-(4b-hydroxy-7-isopropyl -10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl) propane-1-sulfonamide

After dissolving 9b-chloro-4b-hydroxy-7, 8-dimethyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (300 mg, 1.0 mmol) inacetonitrile (ACN) (10 ml, 0.1 M), 1-propane sulfonyl chloride (0.125ml, 1.10 mmol) is added. After pyridine (0.164 ml, 2.03 mmol) is addedat room temperature, stirring is carried out for 10 hours. Uponcompletion of the reaction, concentration under reduced pressure iscarried out. After the concentrated reaction mixture is diluted withethyl acetate (100 ml), it is then washed with water and brine. Water isremoved with Na₂SO₄ and then concentration under reduced pressure iscarried out. Purification is carried at in a silica gel columnchromatography (20%. EA in hexanes) to obtain the target compound (195mg, 48%, yellow solid).

¹H-NMR (300 MHz, CDC 13) δ 0.96 (t, J=7.5 Hz, 3H), 1.18 (dd, J=6.9 Hz,J=4.2 Hz, 6H),1.78-1.91 (m, 2H), 2.42-2.52 (m, 1H), 2.63-2.77 (m, 1H),2.84 (sept, J=6.9 Hz, 1H), 5.50 (s, 1H), 6.22 (s, 1H), 6.77 (s, 1H),6.85 (d, J=7.8 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.54-7.61 (m, 1H),7.77-7.94 (m, 2H), 8.02 (d, J=7.8 Hz, 1H);

402.1 [M+H]+ for LCMS.

EXAMPLE 72 Preparation of 1-chloro-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)methane sulfonamide

After dissolving 9b-chloro-4b-hydroxy-7, 8-dimethyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (300 mg, 1.0 mmol) inacetonitrile (ACN) (10 ml, 0.1 M) at room temperature and then addingchloromethane sulfonyl chloride (0.102 ml, 1.10 mmol), pyridine (0.164ml, 2.03 mmol) is added before stirring is carried out for 10 hours.Upon completion of the reaction, concentration under reduced pressure iscarried out. After the concentrated reaction mixture is diluted withethyl acetate (100 ml), it is then washed with water and brine. Water isremoved with Na₂SO₄ and then concentration under reduced pressure iscarried out. Purification is carried at in a silica gel columnchromatography (20%. EA in hexanes) to obtain the target compound (150mg, 38%, yellow solid).

¹H-NMR (300 MHz, CDC13) δ 1.18 (dd, J=6.9 Hz, J=4.2 Hz, 6H), 2.84 (sept,J=6.9 Hz, 1H), 3.74 (d, J=12.0 Hz, 1H), 4.47 (d, J=12.0 Hz, 1H), 6.75(s, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.55-7.60 (m,1H), 7.76-7.86 (m, 2H), 8.02 (d, J=7.8 Hz, 1H);

408.1 [M+H]+ for LCMS.

EXAMPLE 73 Preparation of 9b-((4,5-dihydro thiazol-2-yl)amino)-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno-[1,2-b]benzofuran-10-one

After dissolving 9b-chloro-4b-hydroxy-7, 8-dimethyl-4b,9b-dihydro-10H-indeno [1,2-b] benzofuran-10-one (315 mg, 1.0 mmol) inTHF (10 ml, 0.1 M) and cooling to −78° C., 2-amino thiazoline chloride(146 mg, 1.05 mmol) is added. TEA (0.307 mL, 2.20 mmol) is added at sametemperature. Stirring is carried out at room temperature for 3 hours.Upon completion of the reaction, concentration under reduced pressure iscarried out. After the concentrated reaction mixture is diluted withethyl acetate (100 ml), it is then washed with water and brine. Water isremoved with Na₂SO₄ and then concentration under reduced pressure iscarried out. Purification is carried at in a silica gel columnchromatography (2:1=EA:hexanes) to obtain the target compound (210 mg,55%).

¹H-NMR (300 MHz, CD30D) δ 1.20 (d, J=6.9 Hz, 6H), 2.83 (sept, J=6.9 Hz,1H), 3.49-3.72 (br, 4H), 6.65 (s, 1H), 6.83 (d, J=7.8 Hz, 1H), 7.17 (d,J=7.8 Hz, 1H), 7.53-7.80 (m, 4H);

381.1 [M+H]+ for LCMS.

EXAMPLE 74 Preparation of 4b-hydroxy-7-isopropyl-9b-(oxazol-2-ylamino)-4b, 9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one

9b-chloro-4b-hydroxy-7-isopropyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (316 mg, 1.00 mmol) is dissolved in THF (10 ml, 0.1M). After adding 3-amino isooxazole (89 mg, 1.05 mmol) and TEA (0.15 ml,1.1 mmol) at −30° C., stirring is carried out at room temperature for 8hours. After concentrating THF and dissolving in DCM, washing is carriedout with water and brine. After extracting organic layers, water isremoved with Na₂SO₄ and then concentration under reduced pressure iscarried out. Purification is carried out in a silica gel columnchromatography to obtain the target compound (50 mg, 14%).

¹H-NMR (300 MHz, CDC13) δ 1.13-1.16 (m, 6H), 2.75-2.85 (m, 1H), 5.37(br, 1H), 5.92 (br, 1H), 6.10 (s, 1H), 6.71 (s, 1H), 6.77 (d, J=7.8 Hz,1H), 7.22 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.2 Hz, 1H), 7.79-7.84 (m, 2H);7.98 (s, 1H), 8.04 (d, J=7.8 Hz, 1H);

363.1 [M+H]+ for LCMS.

EXAMPLE 75 Preparation of 4b-hydroxy-7-isopropyl-9b-(pyridin-2-ylamino)-4b, 9b-dihydro-IOH-indeno[1,2-b]benzofuran-10-one

9b-chloro-4b-hydroxy-7, 8-dimethyl-4b, 9b-dihydro-10H-indeno [1,2-b]benzofuran-10-one (315 mg, 1.0 mmol) is dissolved in THF (10 ml, 0.1 M).After adding 2-amino pyridine (98.5 mg, 1.05 mmol) at −30° C., TEA(0.153 ml, 1.10 mmol) is added. The temperature is raised to normaltemperature and then stirring is carried out for 4 hours. After thereactants are concentrated and diluted with ethyl acetate (100 ml),washing is carried out with water (50 ml×2) and brine (50 ml). Afterextracting organic layers, water is removed with Na₂SO₄ and thenconcentration under reduced pressure is carried out. Purification iscarried out in a silica gel column chromatography (20% EA in hexanes) toobtain the target compound (174 mg, 47%).

¹H-NMR (300 MHz, CDC 13) δ 1.12 (dd, J=6.9 Hz, J=3.0 Hz 6H), 2.76 (sept,J=6.9 Hz, 1H), 5.48 (s, 1H), 6.64-6.75 (m, 4H) 7.16 (d, J=7.8 Hz, 1H),7.43-7.57 (m, 2H), 7.79-7.85 (m, 2H), 7.91 (d, J=4.5 Hz, 1H), 8.07 (d,J=7.8 Hz, 1H), 9.05 (s, 1H);

373.1 [M+H]+ for LCMS

In Table 1 below are listed chemical structural formulae of thecompounds prepared in Examples 1-75 above.

TABLE 1 Example Chemical Structural Formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

EXPERIMENTAL EXAMPLE 1 Determination of Drug Efficacy AgainstPicornaviruses Using Cytopathic Effect (CPE) Inhibition Assay

In the assay, HeLa (human cervical cancer cells), MRC-5 (human fetallung fibroblast cells), and RD cells (derived from humanrhabdomyosarcoma) were employed. For comparison, ribavirin (Riv),Pleconaril (pleco), and BTA-798 (BTA) were used as controls. Reagentswere dissolved at a concentration of 10-40 mg/ml in 100% dimethylsulfoxide (DMSO). Water-soluble reagents were dissolved in PBS (−)solution and stored at −20° C. On the day of the experiment, they wereused in 3 fold to 5 fold concentrations in such a manner that theconcentration of dimethyl sulfoxide in each well was between 0.5% and1%.

Pharmaceutical efficacy was determined using a virus-induced cytopathiceffect (CPE) inhibition assay. In this regard, after cells suitable forviruses were grown in 96-well plates, dilutions of viruses in DMEsupplemented with 2% FBS (DME/2% FBS) or MEM supplemented with 2% FBS(MEM/2% FBS) were inoculated in an amount of 100 ul with a concentrationcorresponding to 100 CCID50 (50% cell culture infective dose) into eachwell of the plates, and incubated for 30 min-1 hr at 33° C. or 37° C. toallow the viruses to adsorb onto the cells. The culture medium wasremoved before aliquots of drug dilutions with various concentrationswere added in an amount of 100 ul to each well. While HRV (humanrhinovirus) was grown at 33° C., the other viruses were incubated in a37° C. CO₂ incubator for 2-3 days. Alternatively, the cells werecultured for 2-3 days without removal of the medium after they wereadded with 50 ul of each drug dilution having a 2-fold higherconcentration and then with 50 ul of the virus dilution

Test conditions for each virus are summarized in Table 2 below:

TABLE 2 Refer- Host Incubation Incubation Virus ence Cell Temp. TermMedium Coxsackie B1 — HeLa 37° C. 2 days DME/2% FBS Coxsackie B3 — HeLa37° C. 2 days DME/2% FBS Poliovirus 3 — HeLa 37° C. 2 days DME/2% FBSRhinovirus — HeLa 37° C. 3 days MEM/2% FBS

For HeLa cells, the drugs were measured for EC₅₀ (50% maximal effectiveconcentration), which is the concentration of a drug inducing a responsehalfway between the baseline and maximum, using an MTT assay. Withregard to RD and MRC-5 cells, CPE was determined using FDA (Fluoresceindiacetate). In order to determine the effect of drug toxicity onefficacy results, at the time of inoculation with the virus, avirus-free medium was added to a cell culture, which was then subjectedto the same treatment as the mock-infected cells inoculated with thevirus. That is, the medium was removed after one hour of incubation, anddilutions of drugs in the medium were added once more. Followingincubation for 2-3 days, the cells were observed under a microscope andthe drugs were determined for CC₅₀ (50% cytotoxic concentration) atwhich 50% of the cells were killed, using an MTT assay in which countsof viable cells in mock-infected wells containing drugs were compared tothose of viable cells in control wells containing no drugs. In an FDAhydrolysis assay, FDA was added to each well after removal of themedium, and incubated for 20-30 min before fluorescence intensity wasmeasured using a spectrofluorometer to determine CPE in the same manneras in MTT.

That is, the survival rate (% survival) of mock-infected cells forcytotoxicity measurement was calculated using the Mathematical Formula 1below:

$\begin{matrix}{{{Cell}\mspace{14mu}{Drug}} = {{Survival}\mspace{14mu}{by}\mspace{14mu}\frac{\begin{matrix}{{A\mspace{14mu}({Drug})} -} \\{A\mspace{14mu}\left( {{Background}\mspace{14mu}{Solution}} \right)}\end{matrix}}{\begin{matrix}{{A\mspace{14mu}\left( {{Cell}\mspace{14mu}{control}} \right)} -} \\{A\mspace{14mu}\left( {{Background}\mspace{14mu} \times 100\%\mspace{14mu}{Solution}} \right)}\end{matrix}}}} & \left\lbrack {{Mathematical}\mspace{14mu}{Formula}\mspace{14mu} 1} \right\rbrack\end{matrix}$

While 100% cell survival means no cytotoxicity of the drug, the highestcytotoxicity is reflected by 0% cell survival. The 50% cytotoxicconcentration was defined as the concentration required to reduce thecell number by 50%. This concentration of the drug is represented asCC₅₀. Higher values mean lower cytotoxicity.

In addition, antiviral effects can be calculated using MathematicalFormula 2 below:

$\begin{matrix}{{{Antiviral}\mspace{14mu}{Effect}} = {\frac{\begin{matrix}{{A\mspace{14mu}\left( {{Drug}/{Virus}} \right)} -} \\{A\mspace{14mu}\left( {{Virus}\mspace{14mu}{Control}} \right)}\end{matrix}}{\begin{matrix}{{A\mspace{14mu}\left( {{Cell}\mspace{14mu}{control}} \right)} -} \\{A\mspace{14mu}\left( {{Virus}\mspace{14mu}{Control}} \right)}\end{matrix}} \times 100\%}} & \left\lbrack {{Mathematical}\mspace{14mu}{Formula}\mspace{14mu} 2} \right\rbrack\end{matrix}$

If the survival rate is 100%, its antiviral effect is 100% whereas ifthe survival rate is 0%, its antiviral effect is none. While theconcentration of a drug at which the cell in a well infected with avirus can exhibit 50% survival rate is calculated as EC₅₀, the lowerthis value is, the more superior the antiviral effect is.

In Table 3 below are listed LC₅₀ concentrations that exhibitcytotoxicity against the compounds in some examples and EC₅₀concentrations that exhibit activities against a number of rhinovirusesbelonging to the picornaviruses.

TABLE 3 CC₅₀ (μg/ml) EC₅₀ (μg/ml) Example Cytotoxicity HRV 14 HRV 21 HRV71 1 7.91 <1.0 >7.91 >7.91 8.57 <0.1 >8.57 >8.57 1.76 >1.76 >1.76 >1.764 9.02 <0.1 >9.02 >9.02 5 8.49 <0.1 >8.49 >8.49 6 8.57 <1.0 >8.57 >8.577 >10.0 <0.1 >10.0 >10.0 8 >10.0 2.31 >10.0 >10.0 93.76 >3.76 >3.76 >3.76 10 4.89 <0.1 >4.89 >4.89 11 7.82 <0.1 3.13 >7.8212 >10.0 2.08 >10.0 >10.0 13 8.41 1.85 >8.41 >8.41 14 8.871.82 >8.87 >8.87 15 8.72 <1.0 >8.72 >8.72 16 >10.0 1.77 >10.0 >10.017 >10.0 6.99 >10.0 >10.0 18 >10.0 >10.0 >10.0 >10.0 19 >10.0<10.0 >10.0 >10.0 20 >10.0 <10.0 >10.0 >10.0 21 >10.0 <1.0 >10.0 >10.022 >10.0 <0.01 <10.0 8.5 23 >10.0 <10.0 >10.0 >10.0 24 >10.0<10.0 >10.0 >10.0 25 2.6 >2.6 >2.6 >2.6 26 >10.0 <10.0 >10.0 >10.027 >10.0 <1.0 >10.0 >10.0 28 >10.0 <10.0 >10.0 >10.0 29 >10.0<1.0 >10.0 >10.0 30 >10.0 >10.0 >10.0 >10.0 31 >10.0 0.012 <10.0 7332 >10.0 <1.0 >10.0 >10.0 33 >10.0 >10.0 >10.0 >10.0 34 >10.0<10.0 >10.0 >10.0 35 >10.0 <10.0 >10.0 >10.0 36 >10.0 <1.0 >10.0 >10.037 >10.0 <0.1 >10.0 >10.0 38 >10.0 <10.0 >10.0 >10.0 39 9.5<10.0 >9.5 >9.5 40 >10.0 <0.1 >10.0 >10.0 41 >10.0 <10.0 >10.0 >10.042 >10.0 <10.0 >10.0 >10.0 43 >10.0 >10.0 >10.0 >10.0 44 n.d n.d n.d n.d45 >10.0 n.d n.d n.d 46 >10.0 >10.0 >10.0 >10.0 47 >10.0<0.1 >10.0 >10.0 48 >10.0 <1.0 >10.0 >10.0 49 >10.0 <0.1 >10.0 >10.050 >10.0 <0.1 >10.0 >10.0 51 >10.0 >10.0 >10.0 >10.0 52 >10.0<0.01 >10.0 >10.0 53 4.8 >4.8 >4.8 >4.8 54 8.6 <1.0 >8.6 >8.6 55 >10.0<10.0 >10.0 >10.0 56 >10.0 >10.0 >10.0 >10.0 57 >10.0 <10.0 >10.0 >10.058 >10.0 <10.0 >10.0 >10.0 59 8.6 <0.1 >8.6 >8.6 60 >10.0<10.0 >10.0 >10.0 61 >10.0 <10.0 >10.0 >10.0 62 >10.0 >10.0 >10.0 >10.063 >10.0 <1.0 >10.0 >10.0 64 >10.0 <10.0 >10.0 >10.0 65 n.d n.d n.d n.d66 n.d n.d n.d n.d 67 n.d n.d n.d n.d 68 n.d n.d n.d n.d 69 n.d n.d n.dn.d 70 n.d n.d n.d n.d 71 n.d n.d n.d n.d 72 n.d n.d n.d n.d 73 n.d n.dn.d n.d 74 n.d n.d n.d n.d 75 n.d n.d n.d n.d

As is indicated in Table 3 above, most of the novel compounds accordingto the present invention exhibit high CC₅₀ concentrations so are foundto have low cytotoxicity. In addition, the novel compounds according tothe present invention were mostly found to have very high antiviralactivities against a number of rhinoviruses (HRV).

Therefore, since the compounds in the example according to the presentinvention exhibit low cytotoxicity and high antiviral activities againstvarious rhinoviruses, they may be usefully used for a pharmacologicalcomposition for preventing or treating diseases caused by thepicornaviruses to which they belong.

EXPERIMENTAL EXAMPLE 2 Determination of Drug Effect AgainstPicornaviruses Using Multicycle Cytopathic Effect (CPE) Reduction Assay

The multicycle CPE reduction assay was used to conduct determination ofdrug efficacy against picornaviruses. The antiviral activity of acompound was initially determined by the CPE reduction assay based onMIS [3-(4, 5-dimethyl thiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.

Specifically, cells grown to confluence in 96-well plates were infectedwith 100 50% cell culture infected doses (CCID₅₀) of virus. After anadsorption period of 2 hrs at 37° C., the virus was removed and serialdilutions of the compounds were added. The cultures were furtherincubated at 37° C. for 3 days until complete CPE was observed in theinfected and untreated virus control (VC). After removal of the medium,90 ul of a culture medium and 10 ul of MTS-phenazine methosulfate(Promega, Leiden, The Netherlands) were added to each well. After anincubation period of 2 hrs at 37° C., the optical density (OD) of eachwell was read at 498 nm in a microplate reader.

The % CPE values for evaluating antiviral activity were calculated usingMathematical Formula 3 below:

$\begin{matrix}{{\%\mspace{14mu}{CPE}} = {100 \times \frac{\begin{matrix}{{{OC}\mspace{14mu}({CC})} -} \\{{OD}\mspace{14mu}\left( {{Virus} + {Compound}} \right)}\end{matrix}}{{{OD}\mspace{14mu}({CC})} - {{OD}\mspace{14mu}({VC})}}}} & \left\lbrack {{Mathematical}\mspace{14mu}{Formula}\mspace{14mu} 3} \right\rbrack\end{matrix}$

The % CPE value for measuring cytotoxicity of a drug was calculated byMathematical Formula 4 below:

$\begin{matrix}{{\%\mspace{14mu}{CPE}} = {100 \times \frac{\begin{matrix}{{{OD}\mspace{14mu}({CC})} -} \\{{OD}\mspace{14mu}\left( {{Virus} + {Compound}} \right)}\end{matrix}}{{{OD}\mspace{14mu}({CC})} - {{OD}\mspace{14mu}({Blank})}}}} & \left\lbrack {{Mathematical}\mspace{14mu}{Formula}\mspace{14mu} 4} \right\rbrack\end{matrix}$

In Mathematical Formulae 3 and 4 above,

OD (CC) represents the OD of the background cell culture that is neitherinduced by a virus nor treated by chemical,

OD (VC) represents the OD of the control cell culture that is induced bya virus but not treated by chemical,

OD (Virus+Compound) represents the OD of the cell culture infected by avirus that has been treated with a concentrated compound,

OD (Compound) represents the OD of the cell culture that has beentreated with a concentrated compound only, and

OD (Blank) represents the OD of the well to which only the cell culturehas been added.

The effective concentration (EC₅₀) represents the concentration of adrug at which 50% of cells are allowed to survive by CPE of an inducedvirus, and the cytotoxicity concentration (CC50) represents theconcentration of a drug at which a compound has killed 50% of cells, andthey were calculated by the logarithmic interpolation.

In Table 4 below are listed the toxicity concentrations (CC₅₀) andeffective concentrations (EC₅₀) against various viruses for somecompounds of the examples.

TABLE 4 CC₅₀ (μg/ml) EC₅₀ (μg/ml) Example Cytotoxicity CoxB1 CoxB3 PV3 18.57 0.017 0.061 1.1 2 9.02 <0.01 <0.01 <1.0 3 2.38 0.013 0.015 <1.04 >10.0 <0.01 <0.01 <1.0 5 >10.0 <0.01 <0.01 <0.1 6 8.57 0.013 0.0151.23 7 >10.0 <0.01 <0.01 <1.0 8 >10.0 0.56 1.82 9.8 9 9.21 0.013 0.015<1.0 10 8.33 <0.01 0.014 <0.1 11 8.72 <0.01 <0.01 <0.1 12 >10.0 0.0150.064 9.8 13 8.31 0.061 0.13 1.98 14 8.57 0.015 0.067 >8.57 15 8.8 <0.01<0.01 <1.0 16 >10.0 0.078 0.33 2.13 17 >10.0 0.033 0.067 2.61 18 >10.0<10.0 <10.0 >10.0 19 >10.0 <1.0 <1.0 <10.0 20 >10.0 <0.1 <0.1 <10.021 >10.0 <0.1 <0.1 <10.0 22 >10.0 <0.01 <0.01 <0.1 23 >10.0 <0.1 <0.1<10.0 24 >10.0 <0.1 <0.1 <10.0 25 9.5 <1.0 <1.0 >9.5 26 >10.0 <10.0<10.0 >10.0 27 >10.0 <0.1 <0.1 <10.0 28 >10.0 <1.0 <10.0 >10.0 29 >10.0<0.1 <0.1 <1.0 30 >10.0 <10.0 <10.0 >10.0 31 >10.0 <0.01 <0.01 <0.132 >10.0 <0.1 <1.0 <10.0 33 >10.0 <10.0 <10.0 >10.0 34 >10.0 <1.0 <10.0<10.0 35 >10.0 <1.0 <1.0 <10.0 36 >10.0 <0.1 <0.1 <10.0 37 >10.0 <0.1<0.1 <10.0 38 >10.0 <1.0 <1.0 <10.0 39 >10.0 <0.1 <0.1 <10.0 40 >10.0<0.01 <0.01 <0.1 41 >10.0 <0.1 <0.1 >10.0 42 >10.0 <0.1 <0.1 >10.043 >10.0 <1.0 <1.0 >10.0 44 >10.0 <0.1 <0.1 <10.0 45 >10.0 <0.1 <0.1<10.0 46 >10.0 <10.0 <10.0 >10.0 47 >10.0 <0.01 <0.1 <0.1 48 >10.0 <0.1<0.1 <10.0 49 >10.0 <0.01 <0.01 <0.1 50 >10.0 <0.1 <0.1 <1.0 51 >10.0<10.0 <10.0 >10.0 52 >10.0 <0.01 <0.01 <0.1 53 >10.0 <10.0 <10.0 >10.054 >10.0 <0.1 <0.1 <10.0 55 >10.0 <1.0 <1.0 >10.0 56 >10.0 <10.0<10.0 >10.0 57 >10.0 <1.0 <1.0 >10.0 58 >10.0 <10.0 <10.0 >10.0 59 >10.0<0.1 <0.1 <0.1 60 >10.0 <1.0 <10.0 >10.0 61 >10.0 <0.1 <1.0 >10.062 >10.0 <10.0 <10.0 >10.0 63 >10.0 <0.1 <0.1 <10.0 64 >10.0 <0.1<0.1 >10.0 65 n.d n.d n.d n.d 66 n.d n.d n.d n.d 67 n.d n.d n.d n.d 68n.d n.d n.d n.d 69 n.d n.d n.d n.d 70 n.d n.d n.d n.d 71 n.d n.d n.d n.d72 n.d n.d n.d n.d 73 n.d n.d n.d n.d 74 n.d n.d n.d n.d 75 n.d n.d n.dn.d

As indicated in Table 4 above, the novel compounds according to thepresent invention mostly exhibit high CC₅₀ concentrations and are foundto have low cytotoxicity. In addition, it was found that the novelcompounds according to the present invention mostly had high antiviralactivities against coxsackievirus B1 (Cox B1), coxsackievirus B3 (CoxB3) and poliovirus 3 (PV3).

Therefore, since the compounds in the examples according to the presentinvention have low cytotoxicity and exhibit superior antiviralactivities against picornaviruses to which coxsackieviruses,polioviruses and rhinoviruses belong, they can be used effectively forprevention or treatment of the diseases caused by such viruses, forexample, respiratory, cardiocirculatory, and nervous system diseases,including poliomyelitis, acute hemorrhagic conjunctivitis, viralmeningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A,myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia,encephalitis, flu, herpangina, foot-and-mouth disease, asthma, chronicobstructive pulmonary disease, pneumonia, sinusitis and otitis media.

FORMULATION EXAMPLE 1 Preparation of Pharmaceutical Formulations

<1-1> Preparation of Powder Agent

Compound expressed in Formula 1 or Formula 2 2 g Lactose 1 g

The above ingredients are mixed and filled in an airtight sac to prepareas a powder agent.

<1-2> Preparation of Tablet

Compound expressed in Formula 1 or Formula 2 100 mg Corn starch 100 mgLactose 100 mg Magnesium stearate  2 mg

The above ingredients are mixed and prepared into tablets according tothe typical method for preparing tablets.

<1-3> Preparation of Capsule

Compound expressed in Formula 1 or Formula 2 100 mg Corn starch 100 mgLactose 100 mg Magnesium stearate  2 mg

The above ingredients are mixed and put into gelatin capsules accordingto the typical method for preparing capsules.

<1-4> Preparation of Injection

Compound expressed in Formula 1 or Formula 2 10 μg/ml Dilutedhydrochloric acid BP Till pH 3.5 is reached Sodium chloride BP forinjection Max 1 ml.

With the sodium chloride BP for injection, an appropriate volume of thecompound is dissolved according to the present invention, dilutehydrochloric acid BP is used to adjust the pH of the solution to a pH3.5, and sodium chloride BP for injection is used to control a volumeprior to sufficient mixing. After the solution is put in a 5-ml type Iampule made of transparent glass, the air is sealed in the upper latticeby melting the glass. Autoclaving and sterilization is carried out at120° C. for at least 15 min to prepare an injection.

INDUSTRIAL APPLICABILITY

As the compounds expressed in Formula 1 or Formula 2 according to thepresent invention that are in equilibria with each other have not onlylow cytotoxicity but also very superior antiviral activities againstpicornaviruses including coxsackieviruses, enteroviruses, echoviruses,polioviruses and rhinoviruses, they can be used effectively aspharmaceutical compositions for prevention or treatment of viral diseasesuch as poliomyelitis, acute hemorrhagic conjunctivitis, viralmeningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A,myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia,encephalitis, flu, herpangina, foot-and-mouth disease, asthma, chronicobstructive pulmonary disease, pneumonia, sinusitis or otitis media.

The invention claimed is:
 1. A method for treating a viral disease in apatient, comprising administering to the patient a compound of Formula 1or Formula 2 below, a pharmaceutically acceptable salt thereof or anoptical isomer thereof;

wherein; R¹ is —H, linear or branched C₁₋₆ alkyl or —NO₂; R² is —H,linear or branched C₁₋₆ alkyl or —NH₂; R³ is —H; R^(4a), R^(4b), R^(4c)and R^(4d) are independently —H or linear or branched C₁₋₆ alkyl; X-L-R⁵is selected from the group consisting of:


2. The method of claim 1, wherein the viral disease is caused bycoxsackievirus.
 3. The method of claim 1, wherein the viral disease iscaused by polio virus.
 4. The method of claim 1, wherein the viraldisease is caused by echovirus.
 5. The method of claim 1, wherein theviral disease is caused by enterovirus.
 6. The method of claim 1,wherein the viral disease is caused by rhinovirus.
 7. The method ofclaim 1, wherein the viral disease is caused by picornavirus.
 8. Themethod of claim 1, wherein the viral disease is poliomyelitis, acutehemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouthdisease, vesicular disease, hepatitis A, myositis, myocarditis,pancreatitis, diabetes, epidemic myalgia, encephalitis, flu, herpangina,foot-and-mouth disease, asthma, chronic obstructive pulmonary disease,pneumonia, sinusitis or otitis media.
 9. A method for treating a viraldisease in a patient, comprising administering to the patient a compoundselected from the group consisting of:N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)-2-(1H-indol -3-yl)-2-oxo acetamide;N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-3-(2-nitrophenyl)-2-oxo propanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopropanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopentanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxooctanamide2-(furan-2-yl)-N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxoacetamide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indol-3-yl)-2-oxoacetamide;N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-3-(4-hydroxyphenyl)-2-oxo propanamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indo1-3-yl)-2-oxoacetamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenylacetamide;N-(4b-hydroxy-7,8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenylacetamide;N-(4b-hydroxy-7,8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-(1H-indo1-3-yl)-2-oxoacetamide;N-(4b-hydroxy-7,8-dimethyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopropanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenylacetamide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-phenylacetamide;N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)-4-(methylthio)-2-oxobutanamide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopropanamide;N1-(2,6-dimethylphenyl)-N2-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)oxalamide;N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2,N2-dimethyloxal amide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopropanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-2-(3,4,5-trimethoxyphenyl)acetamide; (E)-4-(3,4-dimethoxyphenyl)-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxobut-3-enamide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-(2-nitrophenyl)-2-oxopropanamide; N1-(2,6-dimethylphenyl)-N2-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)oxal amide;N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-methyloxal amide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3methyl-2-oxo pentanamide;N-(4b-hydroxy-7-isopryl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-2-oxopentanamide;N1-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2,N2-dimethyloxal amide;N1-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2,N2-dimethyl oxal amide; Ethyl2-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxoacetate; Ethyl2-((4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino-2-oxoacetate;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopentanamide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxooctanamide; Ethyl2-((1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxoacetate;N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3,3-dimethyl-2-oxobutanamide;N-(4b-hydroxyl-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-4-methyl-2-oxopentanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenylbutanamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-3-methyl-2-oxopentanamide;3-bromo-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopropanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2,4-dioxo-4-(pyridyn-4-yl)butanamide;4-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-ylamino)-4-oxo butanoic acid;N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N4,N4-dimethylsuccinamide;N1-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N4-isopropylsuccinamide;N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)cyanamide;N1-(4-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-N2-(2,6-dimethylphenyl)oxal amide;N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-(4-methylpiperazin-1-yl)-2-oxoacetamide;N-(1-amino-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-4-methyl-2-oxo pentanamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxohexanamide;N-(4b-hydroxy-7-isopropyl-1-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2mesityl-2-oxo acetamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxopentanamide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenylbutanamide;N-(1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-mesityl-2-oxoacetamide;N,N′-di-tert-butoxycarbonyl[1]-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]guanidine;Tert-butyl(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)ethan-1,2-diyldicarbamate;4-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-4-oxobutanoic acid;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)2-oxo-2-(3,4,5-trimethoxyphenyl)acetamide;N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-2-oxo-4-phenylbutanamide;N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetimideamide;tert-butyl(2-((4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)amino)-2-oxoethyl)carbamate;2-amino-N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)acetamide;N-tert-butoxycarbonyl[N3-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]guanidine;N,N′-di-tert-butoxycarbonyl[1-(4b-hydroxy-7,8-dimethyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)]-1-methylguanidine;9b-((4,5-dihydrothiazol-2-yl)amino)-4b-hydroxy-7-isopropyl-4b,9b-dihydro-10H-indeno-[1,2-b]benzofuran-10-one;and4b-hydroxy-7-isopropyl-9b-(pyridin-2-yl)amino)-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one;or pharmaceutically acceptable salt thereof or an optical isomerthereof.
 10. The method of claim 9, wherein the viral disease is causedby a rhinovirus.
 11. The method of claim 9, wherein the viral disease iscaused by a coxsackievirus.
 12. The method of claim 9, wherein the viraldisease is caused by a picornavirus.
 13. The method of claim 9, whereinthe viral disease is caused by one of a poliovirus, an echovirus, and anenterovirus.
 14. The method of claim 9, wherein the viral disease ispoliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis,hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis,myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis,flu, herpangina, foot-and-mouth disease, asthma, chronic obstructivepulmonary disease, pneumonia, sinusitis or otitis media.